US007256297B2

(12) United States Patent (10) Patent No.: US 7,256.297 B2 Senanayake et al. (45) Date of Patent: Aug. 14, 2007

(54) METHODS OF PREPARING SULFINAMIDES 7,064.214 B2* 6/2006 Senanayake et al...... 546,339 AND SULFOXDES 7,129,378 B2 * 10/2006 Han et al...... 564,248 2005. O165240 A1 7/2005 Han et al. (75) Inventors: Chris Hugh Senanayake, Shrewsbury MA (US); Zhengxu Han,s Shrewsbury, s OTHER PUBLICATIONS MA (US); Dhilleepkumar Cogan, Derek A et al. Asymmetric Synthesis of Chiral Amines by Krishnamurthy, Westborough, MA Highly Diastereoselective 1.2-Additions of Organometallic (US); Derek Pflum, Northville, MI S. N-tert-Butanesulfinyl Imines. Tetrahedron 55 (1999) systers set Winon. Tang, Tony Pet al. The tert-Butanesulfinyl Group: An Ideal Chiral s Directing Group and Boc-Surrogate for the Asymmetric Synthesis (73) Assignee: Apsinterm, LLC., Wilmington,- DE appd Applicati CaOS O f beta-Aminoal-AO Acids.ACS J. Org.rg. Chem.Unem 1999, 64. (US) Liu, Guangcheng et al. Catalytic Asymmetric Synthesis of tert Butanesulfinamide. Application to the Asymmetric Synthesis of (*) Notice: Subject to any disclaimer, the term of this Amines. J. Am. Chem. Soc. 1997, 119, 9913-9914. patent is extended or adjusted under 35 Davis, Franklin A et al. Concise Asymmetric Synthesis of alpha U.S.C. 154(b) by 0 days. Amino Acid Derivatives from N-Sulfinylimino Esters. J. Org. Chem. 1999, 64, 3396-3397. (21) Appl. No.: 11/340,551 Cogan, Derek A. Catalytic Asymmetric Oxidation of tert-Butyl Disulfide. Synthesis of tert-Butanesulfinamides, tert-Butyl (22) Filed: Jan. 27, 2006 Sulfoxides and tert-Butanesulfinimines. Journal of the American Chemical Society, vol. 120, No. 32, Aug. 19, 1998. O O Owens, Timothy D et al. Synthesis, Utility and Structure of Novel (65) Prior Publication Data Bis(sulfinyl)imidoamidineis ony D et al, Syn Ligands for Asymmetric Lewis Acid US 2006/O128767 A1 Jun. 15, 2006 Catalysis. J. Am. Chem. Soc. 2001, 123, 1539-1540. Kagan, H. Betal. Some Routes to Chiral Sulfoxides with Very High Related U.S. Application Data Enantiomeric Excesses. Synlett 643-650, 1990. - - - Pflum, Derek A et al. Asymmetric Synthesis of Cetirizine (62) Division of application No. 10/120.541, filed on Apr. Dihydrochloride. Tetrahedron Letters 43 (2002) 923-926. 12, 2002, now Pat. No. 7,064,214. Wudl, Fetal, Novel Asymmetric Synthesis of Chiral Sulphoxides. J.C.S. Chem. C 1972, 61-62. (60) Provisional application No. 60/283,337, filed on Apr. Wudl, F ". Aynistric Synthesis of Chiral Sulfoxides. II. An 13, 2001. Intramolecular O -> N Sulfinyl Migration. Journal of the American (51) Int. Cl Chemical Society 95:19 Sep. 19, 1973. 6349-6358. nt. C. CO7D 291/04 (2006.01) * cited by examiner (52) U.S. Cl...... 548/122 Primary Examiner Golam M. M. Shameem (58) Field of Classification Search ...... 548/122 (74) Attorney, Agent, or Firm—Martin A. Hay See application file for complete search history. (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS This invention encompasses novel methods of preparing Sulfinamides and Sulfoxides, particularly stereomerically 4,562,185 A 12/1985 Jager et al. 5,271,812 A 12/1993 Gao et al. pure sulfinamides and sulfoxides. The invention further 5,714,504 A 2/1998 Lindberg et al. encompasses novel compounds from which Sulfinamides 5,776,765 A 7, 1998 Graham et al. and Sulfoxides can be prepared. 5,945,425 A 8, 1999 Moormann et al. 5.948,789 A 9, 1999 Larsson et al. 15 Claims, No Drawings US 7,256.297 B2 1. METHODS OF PREPARING SULFNAMIDES AND SULFOXDES -continued e O R2 R2 This application is a divisional of application Ser. No. 5 S n 4 NHCI 10/120,541 filed on Apr. 12, 2002 now U.S. Pat. No. GE) uk uk" 7,064.214 the entirety of which is incorporated herein by N R - Mott - CIHN R reference, which application Ser. No. 10/120,541 claims priority to U.S. Provisional Application No. 60/283,337, filed Apr. 13, 2001. 10 Few methods of preparing enantiomerically pure Sulfina mides have been reported. See, e.g., Cogan, D. A., et al., J. 1. FIELD OF THE INVENTION Am. Chem. Soc. 120:8011-8019 (1998); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914 (1997). In one method, tert This invention relates to sulfinamides and sulfoxides, butanesulfinamide is prepared by asymmetrically oxidizing methods of their preparation, and compounds that can be 15 tert-butyl disulfide to provide an intermediate, which is then used to prepare them. cleaved by reaction with LiNH. Liu, G. et al., J. Am. Chem. Soc. 119:9913-9914 (1997). Unfortunately, the enantiomeric 2. BACKGROUND OF THE INVENTION purity of the resulting sulfinamide reportedly does not exceed 91%. Id. The method is further limited in that it can 2.1. THE ASYMMETRIC SYNTHESIS OF be used for the synthesis of only a few different kinds of AMINES sulfinamides, of which tert-butanesulfinamide is an example. In addition, this method is not amenable to large At least 75% of drugs and drug candidates reportedly scale, or industrial, production of Sulfinamides. A need incorporate amine functionality. Tang, T. P. and Ellman, J. 25 therefore exits for more efficient and effective methods of A. J. Org. Chem. 64:12-13 (1999). The asymmetric syn preparing a wide variety of Sulfinamides, particularly enan thesis of amines is consequently of particular importance to tiomerically pure sulfinamides. A need further exists for a the pharmaceutical industry. method of preparing sulfinamides that can be adapted to an One method that reportedly can be used to prepare industrial scale. optically active B-amino acids is disclosed in International 30 Application WO 2000/041997. According to this method, a 2.2. THE ASYMMETRIC SYNTHESIS OF compound of the formula RaC*H(OH) C*H(Rb)Rc, SULFOXIDES wherein Rc can be R1SO(R2)N—and theasterisk signifies a chiral center, is reportedly prepared by reacting an O-ami 35 The synthesis of chiral sulfoxides is also important to the nocarbonyl compound of the formula Ra—CO CH(Rb)— pharmaceutical industry. For example, a variety of pharma Rc with hydrogen or a hydrogen donor in the presence of an cologically active benzimidazoles and structurally related optically active transition metal compound and a base. Sulfoxide compounds contain a stereogenic Sulfur atom. Another recently reported method of preparing chiral Examples of Such compounds are shown below in racemic amino acids utilizes Sulfinamides. See, e.g., Tang, T. P. and 40 form: Ellman, J. A. J. Org. Chem. 64:12-13 (1999); Cogen, D. A., et al., Tetrahedron 55:8883-8904 (1999); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914 (1997); Davis, F. A. and FHCO McCoull, W., J. Org. Chem. 64:3396-3397 (1999). In an OCH example of this method, tert-butanesulfinamide condenses 45 with aldehydes and ketones to give tert-butanesulfinyl imi le OCH OUN S N 3 nes in high yields. Tang, T. P. and Ellman, J. A. J. Org. Na Chem. 64:12-13 (1999). These imines can then be contacted with Grignard reagents or organolithiums to provide the e N 2 intermediate shown below in Scheme I, which can then be 50 Pantoprazole sodium Subjected to acidic methanolysis to provide an a-branched amine-hydrochloride product. Id. CH3

N leS N OCH2CF H 55 e N 2 O R2 O= Lansoprazole S R CHO SN NH2 - N - 3 60 OUle CH OCH Oe R2 N l, N es G 2 CH3 65 Nis N R Omeprazole US 7,256.297 B2 3 4 imidazoles that comprise biohydrolyzable moieties such as -continued biohydrolyzable amides, biohydrolyzable esters, biohydro lyzable carbamates, biohydrolyzable carbonates, biohydro N CH3 ly Zable ureides, and biohydrolyzable phosphate analogues. OCsH11 5 Other examples of prodrugs include derivatives of 2-(2- N le N pyridylmethyl)suilfinyl)-benzimidazoles that comprise H i —NO, NO. —ONO, and —ONO, moieties. e Na2 As used herein, the terms “biohydrolyzable carbamate.” “biohydrolyzable carbonate.” “biohydrolyzable ureide.” Rabeprazole 10 "biohydrolyzatle phosphate’ mean a carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the Pantoprazole sodium is sold under the tradename Protonix(R) compound but can confer upon that compound advantageous for the short term treatment of erosive esophagitis associated properties in Vivo, Such as uptake, duration of action, or with gastroesophageal reflux disease (GERD). Physicians ' 15 onset of action; or 2) is biologically less active or inactive Desk Reference, 3439-3442 (55th ed., 2001). Lansoprazole but is converted in vivo to the biologically active compound. is sold under the tradename Prevacid R for the short term Examples of biohydrolyzable carbamates include, but are treatment of active duodenal ulcer. Id. at 3189-3194. Ome not limited to, lower alkylamines, substituted ethylenedi prazole, which is also indicated for the short term treatment amines, aminoacids, hydroxyalkylamines, heterocyclic and of active duodenal ulcer, is sold under the tradename heteroaromatic amines, and polyether amines. Prilosec(R). Id. at 587-591. Finally, rabeprazole is sold under As used herein, the term “biohydrolyzable ester” means the tradename Aciphex(R) for the short term treatment of an ester of a compound that either: 1) does not interfere with erosive or ulcerative GERD, for maintaining healing and the biological activity of the compound but can confer upon reduction in relapse rates of heartburn symptoms in patients that compound advantageous properties in vivo. Such as with erosive or ulcerative GERD, for the short-term healing 25 uptake, duration of action, or onset of action; or 2) is of active duodenal ulcer, and for the long-term treatment of biologically less active or inactive but is converted in vivo pathological hypersecretroy conditions. Id. at 1178-1181. to the biologically active compound. Examples of biohy Various attempts have been made to obtain enantiomeri drolyzable esters include, but are not limited to, lower alkyl cally pure forms of Sulfoxide compounds Such as these. esters, acyl esters (e.g., —C(O)Z, wherein Z is F. C. Br, I), Initial attempts relied on chromatography and the formation 30 alkoxyacyloxy esters, alkyl acylamino alkyl esters, and of chiral salts. See, e.g., U.S. Pat. Nos. 5,693,818 and choline esters. 5,714,504. Methods for the asymmetric syntheses of sulfox As used herein, the term “biohydrolyzable amide” means ides have also been alleged. For example, U.S. Pat. No. an amide of a compound that either: 1) does not interfere 5,776,765 discloses a process that can allegedly be used for with the biological activity of the compound but can confer the enantiomeric synthesis of omeprazole, which comprises 35 upon that compound advantageous properties in vivo. Such the use of a microbial enzyme system to enantioselectively as uptake, duration of action, or onset of action; or 2) is reduce a racemic Sulfoxide compound. See, e.g., col. 12, line biologically less active or inactive but is converted in vivo 57- col. 13, line 67. A method disclosed by U.S. Pat. No. to the biologically active compound. Examples of biohy 5.948,789 comprises the oxidation of a pro-chiral sulphide drolyzable amides include, but are not limited to, lower alkyl using a chiral titanium complex and a base. See, e.g., col. 25. 40 amides, C.-amino acid amides, alkoxyacyl amides, Substi line 64-col. 27, line 8. tuted and unsubstituted ureas, and alkylaminoalkylcarbonyl A need exists for new methods of preparing stereomeri amides. cally pure (e.g., enantiomerically pure) sulfoxides. A par As used herein, the term “pharmaceutically acceptable ticular need exists for efficient and effective methods of salt” refers to a salt prepared from a pharmaceutically preparing enantiomerically pure sulfoxides that can be as acceptable non-toxic inorganic or organic acid. Suitable adapted to an industrial scale. non-toxic acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethene 3. SUMMARY OF THE INVENTION Sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydro chloric, isethionic, lactic, maleic, malic, mandelic, methane This invention is directed, in part, to novel methods of 50 Sulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, preparing Sulfmamides and Sulfoxides, particularly stereo Succinic, Sulfuric, tartaric, and p-toluenesulfonic acids. For merically pure sulfinamides and sulfoxides. The invention example, specific pharmaceutically acceptable salts are further encompasses novel compounds from which sulfina hydrochloride, maleic acid, and tartaric acid salts. mides and Sulfoxides can be prepared. Compounds of this As used herein and unless otherwise indicated, the term invention can be used in the preparation of biologically 55 “alkyl includes saturated linear, branched, and cyclic active (e.g., pharmacologically active) compounds, or are hydrocarbon radicals having 1 to 20 carbon atoms, 1 to 12, themselves biologically active and useful in the treatment or 1 to 8, or 1 to 4 carbon atoms. An alkyl group can include prevention of diseases or conditions in animals (e.g., one or more double or triple bonds or can be substituted with humans). one or more heteroatoms or halogens (e.g., F. Cl, Br, I). It is 60 understood that cyclic alkyl groups comprise at least three 3.1. DEFINITIONS carbon atoms. Specific examples of branched alkyl have one or two branches. Unsaturated alkyl have one or more double As used herein, the term “prodrug means a derivative of bonds and/or one or more triple bonds. Specific examples of a compound that can hydrolyze, oxidize, or otherwise react unsaturated alkyl have one or two double bonds or one triple under biological conditions (in vitro or in vivo) to provide 65 bond. Alkyl chains may be unsubstituted or substituted with the compound. Examples of prodrugs include, but are not from 1 to 4 substituents. Specific examples of substituted limited to, derivatives of 2-(2-pyridylmethyl)sulfinyl)benz alkyl are mono-, di-, or trisubstituted alkyl. Specific US 7,256.297 B2 5 6 examples of alkyl Substituents include halo, haloalkyl, and non-aromatic heterocyclic groups containing one or hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyloxy more heteroatoms each selected from O, S, N, or P. Non carbonylphenyl, halophenyl), heterocyclyl, and heteroaryl. aromatic heterocyclic groups include groups having only 3 As used herein and unless otherwise indicated, the term atoms in their ring system, but aromatic heterocyclic groups “lower alkyl means branched or linear alkyl having from 1 (i.e., heteroaryl groups) must have at least 5 atoms in their to 8 or from 1 to 4 carbon atoms. Examples include, but are ring system. Heterocyclic groups include benzo-fused ring not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, and systems and ring systems Substituted with one or more oxo tertiary butyl. moieties. An example of a 4 membered heterocyclic group As used herein and unless otherwise indicated, the term is azetidinyl (derived from azetidine). An example of a 5 "heteroalkyl means a saturated or unsaturated chain con 10 membered heterocyclic group is thiazolyl, and an example taining carbon and at least one heteroatom, wherein no two of a 10 membered heterocyclic group is quinolinyl. heteroatoms are adjacent. Heteroalkyl chains contain from 1 Examples of non-aromatic heterocyclic groups include, but to 18, 1 to 12, 1 to 6, or 1 to 4 member atoms (carbon and are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahy heteroatoms) in the chain. Heteroalkyl chains may be drothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, pip straight or branched. Specific examples of branched het 15 eridino, morpholino, thiomorpholino, thioxanyl, piperazi eroalkyl have one or two branches. Unsaturated heteroalkyl nyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, have one or more double bonds and/or one or more triple oXepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, bonds. Specific examples of unsaturated heteroalkyl have 1.2.3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, one or two double bonds or one triple bond. Heteroalkyl indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxola chains may be unsubstituted or substituted with from 1 to nyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl. about 4 substituents. Specific examples of heteroalkyl are dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, substituted or unsubstituted. Specific examples of het imidazolidinyl, 3-azabicyclo3.1.0 hexanyl, 3-azabicyclo eroalkyl Substituents include halo, hydroxy, aryl (e.g., phe 4.1.0 heptanyl, 3H-indolyl, quinolizinyl, and substituted nyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophe derivative thereof. Examples of aromatic heterocyclic nyl), heterocyclyl, and heteroaryl. For example, alkyl 25 groups include, but are not limited to, pyridinyl, methylpy substituted with the following substituents are heteroalkyl: ridine analgoues, imidazolyl pyrimidinyl, pyrazolyl, triaz alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy), olyl pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiaz aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, methox olyl, oxazolyl, isothiazolyl pyrrolyl, quinolinyl, yphenoxy, benzyloxy, alkyloxycarbonylphenoxy, acylox isoquinolinyl, indolyl, benzimidazolyl, benzoimidazoles, ypfenoxy), acyloxy (e.g., propionyloxy, benzoyloxy, 30 benzofuranyl, cinnolinyl, indazolyl, indolinyl, indolizinyl, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio. phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, acylthio, arylthio (e.g., phenylthio, chlorophenylthio, alky purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofuraza lphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbon nyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, ylphenylthio), amino (e.g., amino, mono- and di-C-C- quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, alkanylamino, methylphenylamino, methylbenzylamino, 35 and Substituted derivatives thereof. The foregoing groups, as C-C alkanylamido, carbamamido, ureido, guanidino). derived from the compounds listed above, may be C-at As used herein and unless otherwise indicated, the term tached or N-attached where such attachment is possible. For "heteroatom' includes a nitrogen, Sulfur, oxygen, or phos instance, a group derived from benzimidazol can be benz phorus atom. Groups containing more than one heteroatom imidazol-1-yl (N-attached) or benzimidazol-2-yl (C-at may contain different heteroatoms. 40 tached). As used herein and unless otherwise indicated, the term As used herein and -unless otherwise indicated, the term “aryl' includes an organic radical derived from an aromatic "heteroaryl' means an aromatic heterocycle. A heteroaryl is hydrocarbon by removal of one hydrogen, Such as phenyl or an aromatic ring system containing carbon and from 1 to naphthyl. Aryl rings are monocyclic or fused bicyclic ring about 4 heteroatoms in the ring. Heteroaromatic rings are systems. Monocyclic aromatic rings contain from about 5 to 45 monocyclic or fused bicyclic ring systems. Monocyclic about 10 carbon atoms, from 5 to 7 carbon atoms, or from heteroaromatic rings contain from about 5 to about 10, from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings 5 to 7, or from 5 to 6 member atoms (carbon and heteroa contain from 8 to 12 carbon atoms, or 9 or 10 carbon atoms toms). Bicyclic heteroaromatic rings contain from 8 to 129 in the ring. Aromatic rings may be unsubstituted or Substi or 10 member atoms. Heteroaromatic rings may be unsub tuted with from 1 to about 4 substituents on the ring. Specific 50 stituted or substituted with from 1 to about 4 substituents on examples of aromatic ring Substituents include: halo, cyano, the ring. Specific examples of heteroaromatic ring Substitu alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any com ents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, bination thereof More Specific examples of substituents phenyl, phenoxy or any combination thereof. More Specific include halo and haloalkyl. Specific examples of aromatic examples of Substituents include halo, haloalkyl, and phe rings include naphthyl and phenyl. 55 nyl. Specific examples of heteroaromatic rings include thie As used herein and unless otherwise indicated, the term nyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. “aralkyl means an aryl substituted with one or more linear, As used herein and unless otherwise indicated, the term branched, or cyclic alkyl groups. Aralkyl moieties can be “sulfide' includes alkyl groups wherein at least one carbon attached to other moieties through their aryl or alkyl com atom has been replaced with a sulfur atom, and aralkyl ponents. 60 groups wherein at least one non-aromatic carbon atom has As used herein and unless otherwise indicated, the term been replaced with a sulfur atom. “ether includes alkyl groups wherein at least one carbon As used herein and unless otherwise indicated, the term atom has been replaced with an oxygen atom, and aralkyl “substituted as used to describe a compound or chemical groups wherein at least one non-aromatic carbon atom-has moiety means that at least one hydrogen atom of that been replaced with an oxygen atom. 65 compound or chemical moiety is replaced with a second As used herein and unless otherwise indicated, the terms chemical moiety. Examples of second chemical moieties "heterocyclic group' and "heterocycle' include aromatic include, but are not limited to: halogen atoms (e.g., chlorine, US 7,256.297 B2 7 8 bromine, and iodine); C-C linear, branched, or cyclic alkyl polystyrene, TEMPO polystyrene); Polymer-bound phos (e.g., methyl, ethyl, butyl, tert-butyl, and cyclobutyl); phines (e.g., Di(n-butyl)phenylphosphine polystyrene, Di-o- hydroxyl; thiols; carboxylic acids; esters, amides, silanes, tolyl-phenylphosphine polystyrene, Dicyclohexylphe nitriles, thioethers, stannanes, and primary, secondary, and nylphosphine polystyrene, Diphenylphosphinobenzoyl tertiary amines (e.g., -NH2, —NH(CH), —N(CH), and NovaGelTM AM resin, Diphenylphosphinomethyl polysty cyclic amines). Specific examples of second chemical moi rene, Diphenylphosphinopolystyrene, Triphenylphosphine eties are chlorine, hydroxyl, methoxy, amine, thiol, and NovaGelTM, Triphenylphosphine polystyrene); or Polymer carboxylic acid. bound reducing agents (e.g., (Polystyrylmethyl)trimethy As used herein and unless otherwise indicated, a compo lammonium borohydride, (Polystyrylmethyl)trimethylam sition that is “substantially free” of a compound means that 10 monium cyanoborohydride, Dimethylsilyl polystyrene). the composition contains less than about 20% by weight, It should be noted that if there is a discrepancy between more preferably less than about 10% by weight, even more a depicted structure and a name given that structure, the preferably less than about 5% by weight, and most prefer depicted structure is to be accorded more weight. In addi ably less than about 3% by weight of the compound. tion, if the stereochemistry of a structure or a portion of a As used herein and unless otherwise indicated, the term 15 structure is not indicated with, for example, bold or dashed 'stereomerically pure” means a composition that comprises lines, the structure or portion of the structure is to be one stereoisomer of a compound and is Substantially free of interpreted as encompassing all Stereoisomers of it. other stereoisomers of that compound. For example, a Stereomerically pure composition of a compound having one 4. DETAILED DESCRIPTION OF THE chiral center will be substantially free of the opposite INVENTION enantiomer of the compound. A stereomerically pure com position of a compound having two chiral centers will be This invention is directed, in part, to novel methods of substantially free of other diasteroemers of the compound. A preparing Sulfinamides and Sulfoxides. These methods can typical stereomerically pure compound comprises greater be used, for example, to provide Sulfinamides Such as, but than about 80% by weight of stereoisomer of the compound 25 not limited to, stereomerically pure forms of tert-butane Sulfinamide, and Sulfoxides Such as, but not limited to, and less than about 20% by weight of other stereoisomers stereomerically pure forms of compounds disclosed by U.S. the compound, more preferably greater than about 90% by Pat. No. 5,776,765 (e.g., 2-(2-pyridylmethyl)sulfinyl)benz weight of one stereoisomer of the compound and less than imidazoles) and U.S. Pat. No. 5,945,425 (e.g., (H"/K") about 10% by weight of the other stereoisomers of the ATPase inhibitors), both of which are incorporated herein by compound, even more preferably greater than about 95% by 30 reference. weight of one stereoisomer of the compound and less than A first embodiment of the invention encompasses a about 5% by weight of the other stereoisomers of the method of preparing a sulfinamide or Sulfoxide, which compound, and most preferably greater than about 97% by comprises contacting a compound of Formula 1: weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the 35 compound. (1) As used herein and unless otherwise indicated, the term R “enantiomerically pure’ means a stereomerically pure com R NHL position of a compound having one chiral center. Ra As used herein and unless otherwise indicated, the term 40 n o/ "polymer bound' and “polymer bound alkyl or aryl' mean R O-S that the compound of the invention is covalently bound to a R Me polymer support, such as, but not limited to, Merrifield R.' O Resin, See Wang et al., J. Org. Chem, 1977, 42, 1286-1290; Wang Resin, See Fancelli et al., Tetrahedron Lett., 1997, 38. 45 2311-2314; Aminomethyl Resin: MBHA Resin; Amino wherein n is 0 to 3; L is COR or SOR, wherein m is 0 Acid-2-Chlorotrityl Resin: Carboxypolystyrene: 4-Nitro to 3; R and R together form a cyclic structure (e.g., phenyl Carbonate Resin: Oxime Resin; Safety-Catch Resin; substituted or unsubstituted heterocycle or aryl) or each of Alkenyl based resins; Br, C1 functionalized resins; Carbon R and R is independently substituted or unsubstituted ate resins; CHO functionalized resins; CO-H functionalized 50 alkyl, substituted or unsubstituted aralkyl, substituted or resins; Diazonium-based resins: Enol functionalized resins; unsubstituted heteroalkyl, substituted or unsubstituted aryl, NH, NH-NH functionalized resins; OH functionalized res substituted or unsubstituted heterocycle; R and R together ins; Orthogonal photocleavable resins; SH functionalized form a cyclic structure or each of R, and R is indepen resins; Sillylalkyl resins; Silyloxy resins; Triazene-based dently hydrogen, substituted or unsubstituted alkyl, substi resins; Polymer-bound bases (e.g., (Polystyrylmethyl)trim 55 tuted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted ethylammonium bicarbonate, Morpholinomethyl polysty or unsubstituted heterocycle; R and R, together form a rene HL, Piperazinomethyl polystyrene, Piperidine-4-car cyclic structure or each of R and R, is independently boxylic acid polyamine resin, Piperidinomethyl polystyrene, hydrogen, substituted or unsubstituted alkyl, substituted or TBD-methyl polystyrene, Tris-(isonipecotylaminoethyl)- unsubstituted aralkyl, substituted or unsubstituted het amine polystyrene); Polymer-bound coupling reagents (e.g., 60 eroalkyl, substituted or unsubstituted aryl, or substituted or Ethoxycarbonylazocarboxymethyl polystyrene, HOBt-6- unsubstituted heterocycle; and each of R and X is indepen carboxamidomethyl polystyrene, N-Cyclohexylcarbodiim dently a polymer bound alkyl, aryl or heteroalkyl, substi ide.N'-methyl polystyrene); Polymer-bound oxidizing tuted or unsubstituted alkyl, substituted or unsubstituted reagents (e.g., Polystyrylmethyl)trimethylammonium meta aralkyl, substituted or unsubstituted heteroalkyl, substituted periodate, (Polystyrylmethyl)trimethylammonium perruth 65 or unsubstituted aryl, substituted or unsubstituted ether, enate, 4-(Polystyrylmethyloxy)-2.2,6,6-tetramethyl-piperi substituted or unsubstituted ester, substituted or unsubsti din-1-yloxy free radical, 6-(Methylsulfinyl)hexanoylmethyl tuted ketone, Substituted or unsubstituted phosphonate, Sub US 7,256.297 B2 10 stituted or unsubstituted phosphonic acid ester, substituted or unsubstituted phosphinoyl (e.g., -P(=O)(R), wherein -continued R is defined above), substituted or unsubstituted sulfide, 1B R substituted or unsubstituted sulfone, substituted or unsub R stituted sulfinyl imine (e.g., —S(=O)(=NR)—R wherein NHCOR Ra R and R are defined above), substituted or unsubstituted n X heterocycle, or —NRRs, wherein Ra and Rs together with R G/ the nitrogen atom to which they are attached form a hetero O-S cycle or each of R and Rs is independently hydrogen, R Me R" O substituted or unsubstituted alkyl, substituted or unsubsti 10 tuted heteroalkyl, substituted or unsubstituted aralkyl, sub stituted or unsubstituted aryl, substituted or unsubstituted In another method of this embodiment, M of the formula ether, substituted or unsubstituted sulfide, or substituted or MY is Al, Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, or Cu; in unsubstituted heterocycle: another method, M is of the formula CdZ, BaZ, Mg2, Zinz, with a compound of the formula MY, wherein M is a 15 AlZ, Mnz. InZ, or CuZ, wherein Z is Cl, Br, I, aryl, aralkyl, metal or metal complex capable of transferring Y to the or heterocycle. positively charged Sulfur atom of the compound of Formula In another method, the compound of Formula 1 is pre 1 and Y is independently substituted or unsubstituted alkyl, pared by contacting a compound of Formula 3: substituted or unsubstituted aralkyl, substituted or unsubsti tuted heteroalkyl, substituted or unsubstituted aryl, substi tuted or unsubstituted ether, substituted or unsubstituted (3) ester, substituted or unsubstituted ketone, substituted or R L unsubstituted phosphonate, substituted or unsubstituted R A phosphonic acid ester, Substituted or unsubstituted phosphi Ra ), Gy-ON noyl, substituted or unsubstituted sulfide, substituted or 25 unsubstituted sulfone, substituted or unsubstituted sulfinyl R c/ imine, substituted or unsubstituted heterocycle, or is of the R formula —NRR7, wherein R and R, together with the R" nitrogen atom to which they are attached form a heterocycle or each of R and R, is independently a polymer bound 30 alkyl, aryl or heteroalkyl; hydrogen; Substituted or unsub wherein n is 0 to 3; L is COR or SOR, wherein m is 0 stituted alkyl; substituted or unsubstituted aralkyl; substi to 3; and R. R. R. R., and Rs are defined above; tuted or unsubstituted heteroalkyl; substituted or unsubsti with a compound of the formula MX, wherein M' is a tuted aryl; substituted or unsubstituted ether; substituted or metal or metal complex capable of transferring X to the unsubstituted ester; substituted or unsubstituted ketone; sub 35 positively charged Sulfur atom of the compound of Formula stituted or unsubstituted phosphonate; substituted or unsub 3 and X is defined above. stituted phosphonic acid ester; substituted or unsubstituted In a preferred embodiment, the compounds of Formula 3 phosphinoyl; substituted or unsubstituted sulfide; substituted have the following structures: or unsubstituted sulfone; substituted or unsubstituted sulfi nyl imine; substituted or unsubstituted heterocycle; under 40 conditions suitable for the formation of a compound of 3A Formula 2: R i? SORs R M

R 3. N (2) o'S-O 45 R c/ R R.' 3B Ri' COR 50 R / wherein X and Y are defined above. R 3. N In a preferred method of this embodiment, the ey-O compound(s) of Formula 1 and/or Formula 2 is/are stereo R c/ merically pure. R In another preferred embodiment, the compounds of For 55 R" mula 1 have the following structures: In a preferred method of this embodiment, M of the 1A formula MX is Al, Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, or R 60 Cu; in another method, M' is of the formula CdZ, BaZ, R Mgz, Zinz, AIZ Mnz, Inz, or CuZ, wherein Z is Cl, Br, Ra NHSOR2TV-3 I, aryl, aralkyl, or heterocycle or a combination with a Lewis )n X acid, such as, but not limited to, Ti(OPr) or Ti(OR)Cl. R O e/ where R is defined above. R Ve 65 In another preferred method of this embodiment, X is R.' O tert-butyl, trialkylmethyl, triheteroalkylmethyl, triarylm ethyl, triheteroarylmethyl, triheterocyclemethyl, aryl, het US 7,256.297 B2 11 erocyclic, heteroaryl, alkyltrialkyl, alkylheteroalkylmethyl, diarylalkylmethyl, adamantyl, dialkyladamantyl, trialky laryl, triethylmethyl, dimethylethyl, trimethylphenyl, tri R R alkylphenyl, triisopropylphenyl, polymer bound alkyl or R NHSOR R NHSORs 5 aryl or is of Formula 4: or is of Formula 4: X X G)/ / R O- v R O v. R O R G (4) 2 O 2 O R R 10 R NHSOR R NHSORs A4 X X GE) M ' GE) / R O-S. R O-S. R2 2O e R2 2O (e 15 R R or a salt thereof, wherein each Rs is independently substi R NHSOR RINNHSO2R3 tuted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted X X (9/ Ge/ or unsubstituted aryl, substituted or unsubstituted ether, R O-S R O-S. R O R 2 e substituted or unsubstituted sulfide, substituted or unsubsti 2 O 2 O tuted heterocycle, a primary, secondary, or tertiary amine, or R R a halogen atom; and p is an integer of 0 to 4, or is of Formula R NHSOR RINNHSO2R3 5: X X 25 M Ge/ R O-S R O-S (5) R.' , G R.' O G N

Na2 30 In another preferred method of this embodiment, the compound of Formula 1 has one of the following structures: wherein each R is independently substituted or unsubsti NHSOR NHSOR tuted alkyl, substituted or unsubstituted heteroalkyl, substi tuted or unsubstituted aralkyl, substituted or unsubstituted 35 X N aryl, substituted or unsubstituted ether, substituted or unsub O-SGe/ 1. V G stituted sulfide, substituted or unsubstituted heterocycle, a \le eX S-X O (R10)m / primary, secondary, or tertiary amine, or a halogenatom; and Oe q is an integer of 0 to 4. Preferably, q is 2 or 3. 40 If X is of Formula 4. p is preferably 0 or 1. If p is 1. Rs is preferably OCH or —OCHF. If X is of Formula 5 and wherein X and R are each defined above and each Ro is q is 2, each R is preferably —CH, OCH —OCHCF, independently substituted or unsubstituted alkyl, substituted or —OCH; if q is 3, R is preferably —CH or —OCH. or unsubstituted aralkyl, substituted or unsubstituted aryl, In another preferred method of this embodiment, Y is 45 substituted or unsubstituted ether, substituted or unsubsti —NRR, or is of Formula 4 or Formula 5. If Y is of Formula tuted Sulfide, a primary, secondary, or tertiary amine, a 4. p is preferably 0 or 1. If p is 1, R is preferably —OCH heterocycle, or a halogen atom; n is an integer of 1 to 4; and or —OCHF. If Y is of Formula 5 and q is 2, each R is m is an integer of 0 to 4. In a preferred method, n is 1 and preferably —CH —OCH —OCHCF, or —OCH; if m is 0, 1, or 2, and wherein R is tert-butyl, trialkylmethyl, 50 triheteroalkylmethyl, triarylmethyl, triheteroarylmethyl, tri q is 3, R is preferably —CH or —OCH. heterocyclemethyl, aryl, heterocyclic, heteroaryl, alkyltri In another preferred method of this embodiment, R is alkyl, alkylheteroalkylmethyl, diarylalkylmethyl, adaman aryl or aklyl. In a more preferred method, R is methyl. tyl, dialkyladamantyl, trialkylaryl, triethylmethyl, In another preferred method of this embodiment, R is dimethylethyl, trimethylphenyl, trialkylphenyl, triisopropy aryl or alkyl. In a more preferred method, R is phenyl. 55 lphenyl, polymer bound alkyl or aryl or is of Formula 4: In another preferred method of this embodiment, R is a substituted or unsubstituted heteroalkyl, substituted or unsubstituted lower alkyl (e.g., halogenated phenyl, 3-me (4) thylphenyl, 4-methylphenyl, 1,3,5-trimethylphenyl, (tert N butyl)phenyl, 2-mesityl, tolyl, or 1,3,5-triisopropylphenyl), 60 or aryl (e.g., phenyl and biphenyl). In a more preferred method, R is 2-mesityl, tolyl, tri-isopropyl, or a polymer - bound aryl or alkyl. In a preferred method of this embodiment, the compound 65 of Formula 1 is stereomerically pure and has one of the or a salt thereof, wherein each Rs is independently substi following stereochemistries: tuted or unsubstituted alkyl, substituted or unsubstituted US 7,256.297 B2 13 14 aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, Sub stituted or unsubstituted heterocycle, a primary, secondary, (5) or tertiary amine, or a halogen atom; and p is an integer of 5 0 to 4; or is of Formula 5: "rnN-4| --(R), (5) 10 wherein each R is independently substituted or unsubsti "rn| --(R), tuted alkyl, substituted or unsubstituted aralkyl, substituted N4 or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, substituted or unsubsti 15 tuted heterocycle, a primary, secondary, or tertiary amine, or wherein each R is independently substituted or unsubsti a halogen atom; and q is an integer of 0 to 4. In another tuted alkyl, substituted or unsubstituted aralkyl, substituted preferred method, at least one of R and R, is hydrogen. In or unsubstituted aryl, substituted or unsubstituted ether, yet another preferred method, Re and R7 are both hydrogen. substituted or unsubstituted sulfide, substituted or unsubsti In another preferred method of this embodiment, the tuted heterocycle, a primary, secondary, or tertiary amine, or compound of Formula 3 has one of the following stere a halogen atom; and q is an integer of 0 to 4. In a preferred ochemistries: method, the compound of Formula 6 or 7 is stereomerically pure. 25 R i SOR2r.3 R i SOR2r.3 R M R M In a preferred method of this embodiment, the compound N vN of Formula 2 is of Formula 8, stereoisomers of which are N O N GS-O GES II IO shown below: R o/ R ino? 30 R R.' R i SOR2r.3 R i SOR2r.3 oe O O R M R M V s N wN 1SN 1Sn N N O RRN () X RRN () X GES II IO GS-O 35 R c/ R ino? 8(S) 8(R) R R.'

R i SOR2r.3 R i SOR2r.3 R M R M In a particularly preferred method of this embodiment, X wN N is phenyl, 4-methylphenyl, tert-butyl, adamantyl, trimeth 40 N N ylphenyl, pyridyl, or trialkylmethyl, triisopropylphenyl, tri GS-O GS-O alkyl phenyl, tetraacylphenyl, or pentaalkylphenyl, trihet R o/ R "no? eroalkylmethyl, triarylmethyl, triheteroarylmethyl, R R" triheterocyclemethyl, aryl, heterocyclic, heteroaryl, alkyltri 45 R R MSO2R3 R R MSO2R3 alkyl, alkylheteroalkylmethyl, diarylalkylmethyl, dialky wN. N ladamantyl, trialkylaryl, triethylmethyl, dimethylethyl, tri esmo esmo alkylphenyl, triisopropylphenyl, polymer bound alkyl or R o/ R "uno? aryl or is of Formula 4: R R.' 50

(4) In a particularly preferred method of this embodiment, the compound of Formula 3 has one of the following structures:

55 N (9) or a salt thereof, wherein each Rs is independently substi 60 tuted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, Sub stituted or unsubstituted heterocycle, a primary, secondary, 65 or tertiary amine, or a halogen atom; and p is an integer of 0 to 4; or is of Formula 5: US 7,256.297 B2 15 16

-continued (10) (13) SOR3 FHCO O N.N.1° 5 N oi Ol le OCH OCH O Sir NY ex Prot O O N S. 10 and optionally contacting the compound of Formula 13 with wherein R. R. m., and n are defined herein. a reagent capable of replacing Prot with a hydrogen atom or With regard to compound 10, when n is 1, the stereochem a cation (e.g., Na' or K). Suitable reagents include, but are istry of the compound is preferably cis, two isomers of 15 not limited to NaOH, KOH, or a mild acid followed by NaH which are shown below: or KH. In a preferred method, the compound of Formula 1 1 is prepared by contacting a compound of Formula 3 with a compound of Formula 14:

(14) FHCO 25

30 wherein M' is defined herein, under conditions sufficient for the formation of the compound of Formula 1 1. In another preferred method, the compounds of formulas A specific method of this embodiment is a method of 35 11 and 13 are enantiomerically pure. preparing pantoprazole, or a derivative, prodrug, salt, Sol Another specific method of this embodiment is a method vate, clathrate, or stereomerically pure form thereof, which of preparing lansoprazole, or a derivative, prodrug, salt, comprises contacting a compound of Formula 11: solvate, clathrate, or stereomerically pure form thereof, 40 which comprises contacting a compound of Formula 15: (11) R (15) R NHSOR R R NHSOR e Prot 45 / e Prot R O-S N / R" () R O-S N N R. () OCHF 50 N wherein R. R. R., and R are defined herein, and Prot is a protecting group (e.g., an animal or Sulfanamide), with a wherein R. R. R. R., and Prot are defined herein, with a compound of Formula 12: 55 compound of Formula 16:

(12) (16) OCH OCH2CF H3CO N 60

M 2 N

65 wherein M is defined herein, under conditions suitable for wherein M is defined herein, under conditions suitable for the formation of a compound of Formula 13: the formation of a compound of Formula 17: US 7,256.297 B2 17 18

(17) (21) CH3 H3CO CH3 leSt. NY OCH2CF le OCH Prot O O N S St. NY Prot O N 10 O N CH3 and optionally contacting the compound of Formula 17 with a reagent capable of replacing Prot with a hydrogen atom or and optionally contacting the compound of Formula 21 with a reagent capable of replacing Prot with a hydrogen atom or a cation. 15 In a preferred method, the compound of Formula 15 is a cation. prepared by contacting a compound of Formula 3 with a In a preferred method, the compound of Formula 19 is compound of Formula 18: prepared by contacting a compound of Formula 3 with a compound of Formula 22:

(18) (22) H3CO

25

wherein M' is defined herein, under conditions sufficient for 30 the formation of the compound of Formula 15. wherein M' is defined herein, under conditions sufficient for In another preferred method, the compounds of formulas the formation of the compound of Formula 19. 15 and 17 are enantiomerically pure. In another preferred method, the compounds of formulas Another specific method of this embodiment is a method 35 19 and 21 are enantiomerically pure. of preparing omeprazole, or a derivative, prodrug, salt, Still another specific method of this embodiment is a solvate, clathrate, or stereomerically pure form thereof, method of preparing rabeprazole, or a derivative, prodrug, which comprises contacting a compound of Formula 19: salt, Solvate, clathrate, or stereomerically pure form thereof, which comprises contacting a compound of Formula 15: 40 (19) R (15) R NHSOR R R NHSOR e Prot 45 / e Prot R O-S N / R" GE) R O-S N R. G. N OCH 50 N wherein R. R. R. R., and Prot are defined herein, with a wherein R. R. R. R., and Prot are defined herein, with a compound of Formula 20: compound of Formula 23: 55

(20) (23) OCH OC5H1 CH 60

65 wherein M is defined herein, under conditions suitable for wherein M is defined herein, under conditions suitable for the formation of a compound of Formula 21: the formation of a compound of Formula 24: US 7,256.297 B2 19 20 ylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl, or 2.4.6- triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In (24) more preferred compounds, R is 2-mesityl or tolyl. CH 3 In other preferred compounds of Formula 7, each Ro is 5 independently substituted or unsubstituted alkyl, substituted lei 21 OCH51 or unsubstituted aralkyl, or substituted or unsubstituted aryl. In more preferred compounds of Formula 7, each Ro is Prot O G N N independently alkyl, aralkyl, or aryl. In preferred compounds of Formula 7, n is 1 and m is 0. 10 1, or 2. and optionally contacting the compound of Formula 24 with Preferred compounds of Formula 7 are stereomerically a reagent capable of replacing Prot with a hydrogen atom or pure. a cation. The invention further encompasses compounds of For In a preferred method, the compound of Formula 15 is mula 25: prepared by contacting a compound of Formula 3 with a 15 compound of Formula 18: (25) R NHSOR (18) e R12 R O s( 2 GE) Y 21 (R1 Dr N N 25 and salts, Solvates, clathrates, and stereomerically pure wherein M' is defined herein, under conditions sufficient for forms thereof, wherein R and R together form a cyclic the formation of the compound of Formula 23. structure (e.g., Substituted or unsubstituted heterocycle or In another preferred method, the compounds of formulas 30 aryl) or each of R and R is independently substituted or 23 and 25 are enantiomerically pure. unsubstituted alkyl, substituted or unsubstituted aralkyl, A second embodiment of the invention encompasses Substituted or unsubstituted aryl, or substituted or unsubsti various compounds that are particularly useful for the prepa tuted heterocycle; R is substituted or unsubstituted alkyl, ration of sulfinamides and sulfoxides. For example, the substituted or unsubstituted aralkyl, substituted or unsubsti invention encompasses compounds of Formula 7: 35 tuted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, substituted or unsubstituted hetero cycle, or —NRRs, wherein R and Rs together with the (7) nitrogen atom to which they are attached form a heterocycle NHSOR or each of R and Rs is independently hydrogen, Substituted 40 or unsubstituted alkyl, substituted or unsubstituted aralkyl, O substituted or unsubstituted aryl, substituted or unsubstituted O ether, substituted or unsubstituted sulfide, or substituted or w S-C(CH) (R10)m W unsubstituted heterocycle; each R is independently Substi Oe tuted or unsubstituted alkyl, substituted or unsubstituted 45 aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, a and salts, Solvates, clathrates, and stereomerically pure primary, secondary, or tertiary amine, a heterocycle, or a forms thereof, wherein R is independently substituted or halogen atom; R is Substituted or unsubstituted alkyl, unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aralkyl, substituted or unsubsti substituted or unsubstituted aryl, substituted or unsubstituted 50 tuted aryl, substituted or unsubstituted ether, substituted or ether, substituted or unsubstituted sulfide, substituted or unsubstituted sulfide, or substituted or unsubstituted hetero unsubstituted heterocycle, or —NRRs, wherein Ra and Rs cycle, or is a Sulfoxide; and r is an integer from 0 to 4. together with the nitrogen atom to which they are attached In preferred compounds of Formula 25, n is 1 m is 0, 1, form a heterocycle or each of R and Rs is independently or 2, and r is 2 or 3. hydrogen, is independently substituted or unsubstituted 55 In additional preferred compounds of Formula 25, R is alkyl, substituted or unsubstituted aralkyl, substituted or phenyl or lower alkyl. In a particular compound, R is unsubstituted aryl, substituted or unsubstituted ether, sub methyl. stituted or unsubstituted sulfide, or substituted or unsubsti In additional preferred compounds of Formula 25, R is tuted heterocycle; each Ro is independently substituted or phenyl or lower alkyl. In a particular compound, R is unsubstituted alkyl, substituted or unsubstituted aralkyl, 60 phenyl. substituted or unsubstituted aryl, substituted or unsubstituted In additional preferred compounds of Formula 25, R is a ether, Substituted or unsubstituted Sulfide, a primary, sec substituted or unsubstituted lower alkyl, substituted or ondary, or tertiary amine, a heterocycle, or a halogen atom; unsubstituted aralkyl (e.g., halogenated phenyl, 3-meth n is an integer of 1 to 4; and m is an integer of 0 to 4. ylphenyl, 4-methylphenyl, 1,3,5-trimethylphenyl, (tert-bu In preferred compounds of Formula 7, R is a substituted 65 tyl)phenyl, 2-mesityl, tolyl, or 1,3,5-triisopropylphenyl), or or unsubstituted lower alkyl, substituted or unsubstituted aryl (e.g., phenyl and biphenyl). In a particular compound, aralkyl (e.g., halogenated phenyl, 3-methylphenyl, 2-meth R is 2-mesity1 or tolyl. US 7,256.297 B2 21 22 Specific preferred compounds of Formula 25 are those of Preferred compounds of Formula 9 are stereomerically Formula 26: pure. The invention further encompasses compounds of For mula 10: (26) 5 ". (10) \ / NHSOR SOR3 e R12 10 O- s GE) 21 T- (R1 Dr N N 15 and salts, Solvates, clathrates, and stereomerically pure and salts, Solvates, clathrates, and stereomerically pure forms thereof, wherein each R is independently substituted forms thereof, wherein R is substituted or unsubstituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, alkyl, substituted or unsubstituted aralkyl, substituted or substituted or unsubstituted aryl, substituted or unsubstituted unsubstituted aryl, substituted or unsubstituted ether, sub ether, Substituted or unsubstituted Sulfide, a primary, sec stituted or unsubstituted sulfide, substituted or unsubstituted ondary, or tertiary amine, a heterocycle, or a halogen atom; heterocycle, polymer bound alkyl or aryl, or —NRRs, R is substituted or unsubstituted alkyl, substituted or wherein Ra and Rs together with the nitrogen atom to which unsubstituted aralkyl, substituted or unsubstituted aryl, sub they are attached form a heterocycle or each of R and Rs is stituted or unsubstituted ether, substituted or unsubstituted 25 independently hydrogen, Substituted or unsubstituted alkyl, sulfide, or substituted or unsubstituted heterocycle, or is a substituted or unsubstituted aralkyl, substituted or unsubsti Sulfoxide; and r is an integer from 0 to 4. tuted aryl, substituted or unsubstituted ether, substituted or In preferred compounds of Formula 26, R2 is a protecting unsubstituted sulfide, or substituted or unsubstituted hetero group. cycle; each Ro is independently Substituted or unsubstituted In preferred compounds of Formula 26, each R is 30 alkyl, substituted or unsubstituted aralkyl, substituted or independently substituted or unsubstituted alkyl or substi unsubstituted aryl, a primary, secondary, or tertiary amine, tuted or unsubstituted ether. or a halogen atom; n is an integer of 1 to 4; and m is an In preferred compounds of Formula 26, n is 1 m is 0, 1, integer of 0 to 4. or 2, and r is 2 or 3. In preferred compounds of Formula 10, R is a substituted The invention further encompasses compounds of For 35 or unsubstituted lower alkyl, substituted or unsubstituted mula 9: aralkyl (e.g., halogenated phenyl, 3-methylphenyl, 2-meth ylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl, or 2.4.6- triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In (9) more preferred compounds, R is 2-mesityl or tolyl. 40 In other preferred compounds of Formula 10, n is 1 and m is 0, 1, or 2. Preferred compounds of Formula 10 are stereomerically pure. 45 Also encompassed by the invention are compounds oil Formula 56: and salts, Solvates, clathrates, and stereomerically pure (56) forms thereof, wherein R is substituted or unsubstituted 50 alkyl, substituted or unsubstituted aralkyl, substituted or G unsubstituted aryl, substituted or unsubstituted ether, sub O stituted or unsubstituted sulfide, substituted or unsubstituted N heterocycle, polymer bound alkyl or aryl, or —NRRs, V wherein R and Rs together with the nitrogen atom to which 55 SOR3 they are attached form a heterocycle or each of R and Rs is independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubsti and salts, Solvates, clathrates, and stereomerically pure tuted aryl, substituted or unsubstituted ether, substituted or forms thereof, wherein R is substituted or unsubstituted unsubstituted sulfide, or substituted or unsubstituted hetero 60 alkyl, substituted or unsubstituted aralkyl, substituted or cycle. unsubstituted aryl, substituted or unsubstituted ether, sub In preferred compounds of Formula 9, R is a substituted stituted or unsubstituted sulfide, substituted or unsubstituted or unsubstituted lower alkyl, substituted or unsubstituted heterocycle, polymer bound alkyl or aryl, or —NRRs, aralkyl (e.g., halogenated phenyl, 3-methylphenyl, 2-meth wherein R and Rs together with the nitrogen atom to which ylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl, or 2.4.6- 65 they are attached form a heterocycle or each of R and Rs is triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In independently hydrogen, Substituted or unsubstituted alkyl, more preferred compounds, R is 2-mesity1 or tolyl. substituted or unsubstituted aralkyl, substituted or unsubsti US 7,256.297 B2 23 24 tuted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, or substituted or unsubstituted hetero -continued cycle. R NHSOR In preferred compounds of Formula 56, R is a substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g., halogenated phenyl, 3-methylphenyl, 2-meth R OH ylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl, or 2.4.6- (28) (2) triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In more preferred compounds, R is 2-mesity1 or tolyl. 10 As shown in Scheme II, a compound of Formula 27 is Preferred compounds of Formula 56 are stereomerically contacted with a compound of the formula HalSOR, pure. wherein Hal is halogen and R. R. and R are defined herein, under conditions suitable for the formation of a 4.1. PREPARATION OF SULFINAMIDES AND compound of Formula 28. Examples of HalSOR include, SULFOXIDES 15 but are not limited to, p-toluenesulfonyl chloride and mesi tylsulfonyl chloride. As those of skill in the art will recog In general, Sulfinamides and Sulfoxides are prepared nize, the particular conditions sufficient for this reaction to according to this invention by contacting a compound of occur will depend on the specific compounds being reacted. Formula 1: Suitable conditions will be readily apparent to the skilled chemist. In one example, triethylamine is used with a (1) R solvent such as, but not limited to, methylene chloride. R NHSOR The compound of Formula 28 is then contacted with a reagent capable of forming a five-membered ring to provide X 25 ()/ compound 3. One example of such a reagent is SOCl with R O-S R.' Ve a base in a suitable solvent. Examples of bases include, but O are not limited to, trialkylamines (e.g., triethylamine), pyri dine, imidazole, quinoline, and derivatives thereof. wherein R. R. R. R. R. and X are defined herein, with 30 Examples of suitable solvents include, but are not limited to, a reagent that will cleave the Sulfur-oxygen bond to provide THF, methyl-THF, CHC1, CICHCHCl, toluene, chlo a compound of Formula 2: robenzene, dichlorobenzene, dioxanes, MTBEATHF, DME, and other solvent mixtures. Another example of a reagent (2) G that can be used to form the compound of Formula 3 is O 35 2.4.6-collidine or a Substituted pyridine or pyridine analogue in a solvent such as, but not limited to, THF. y1 Nx The effects of various reagents and reaction conditions on the formation and stereochemistry of specific compounds of In preferred methods of the invention, the compounds of 40 Formula 3 shown below, are provided in Table 1: formulas 1 and 2 are stereomerically pure. A particular method of the invention is shown below in TABLE 1. Scheme II: jok G) jok O 45 Rio" NNMO Rio" N.N. O Scheme II ai". ai-N. R NH2 R NHSOR O O HalSOR3 He Hal = Cl, Br, or I R OH R OH Rio R10' (27) (28) (endo) (exo) Rio Endo:Exo (solvent and at -45° C. unless R Ro" in Base otherwise indicated) R NHSOR SOR3 4-methylphenyl H 1 Triethylamine 75:25 (THF) 1 Triethylamine 62:38 X MX G) (THF/CH2Cl 1:1) G / -e- GES-O 1 Triethylamine 87:13 (CHCN) R OS OM 60 1 Triethylamine 73:27 (EtOAc) ye R 1 Imidazole 70:30 (THF) O 1 1-Methylimidazole 75:25 (THF) 1 Pyridine 75:25 (THF) (3) 1 2.6-Lutidine 85:15 (THF) 1 2.4.6-Collidine 91:9 (THF) 65 1 2,6-Di-t- 3:97 (THF) Butylpyridine US 7,256.297 B2 25 26 Sulfoxides and Sulfinamides, and stereomerically pure Sul TABLE 1-continued foxides and Sulfinamides in particular. For example, when MY is NHLi/NH, this method can be used to provide Rin" jok OG Rin" jok O 5 Stereomerically pure alkyl (e.g., tert-butyl), aryl (e.g., tolyl), O NN M O NN S heteroalkyl (e.g., tert-butyl amino), heterocyclic (e.g. tet ai".O Gin.O rahydrofuryl, or heteroaryl (e.g., pyridyl) sulfinamide. Specific methods of the invention, which can be used to 10 prepare enantiomerically pure pantoprazole, lanSoprazole, Rio Rio omeprazole, and rabeprazole, and pharmaceutically accept (endo) (exo) able salts, Solvates, clathrates, hydrates, prodrugs, and Ste reomerically pure forms thereof, are represented below in Rio Endo:Exo (solvent schemes III-VI, respectively. In each scheme, the stere and at -45° C. unless 15 R Ro" Base otherwise indicated) ochemistry of the compound of Formula 3 is different in 4-Me-2,6-t-Bu- 20:80 order to emphasize that the stereochemistry of the final pyridine (THF) (-20° C.) product can be varied by simply altering the corresponding 4-t-Butylpyridiene 84.3:15.7 (THF) 2,6- 15.8:842 Stereochemistry of the starting material. As with all schemes Dimethoxypyridine (CH2Cl2, 0° C.) disclosed herein, those shown below are provided by way of Quinaldine 87:13 (THF) Lepidine 88:12 (THF) illustration, and are not to be construed as limiting the scope CH Pyridine 97.3 (THF) of the invention. H Pyridine 97.3 (THF) 4-Picoline 78:22 (THF) 2-mesityl H Triethylamine 85:15 (THF) 25 Scheme III Triisopropylamine 66.7:33.3 (THF) Diethylaniline 2:98 FHCO (CH2Cl2, -15° C.) Diethylaniline 37:63 (THF, -20° C.) J N M Triphenyamine No reaction 30 midazole 82:18 (THF) R , O.R. 2-Methylimidazole 85.7:14.3 (THF) R N Prot 2-Ethylimidazole 66:33 14 Pyridine 90:10 (THF) (s-o (14) 2-Phenylpyridine 83:17 (THF) R O 2,4,6-Collidine 93.7 (THF) 35 2,6- 2:98 R" Dimethoxypyridine (CH2Cl2, -15° C.) 2,6- 75:25 (3) Dimethoxypyridine (THF, -45° C. - rt) Lepidine 94:6 (THF) OCH 2,4,6-triisopropyl H Triethylamine 87:13 (THF) R HCO phenyl R NHSOR 3 N 2,4,6-Collidine 95:5 (THF) O Prot M a 4-t-butylphenyl H Triethylamine 80:20 (THF) p N Triethylamine 40:60 (CH2Cl2) R O-S N 4-methylphenyl CH Triethylamine 85.7:14.3 R" &Y He(12) (CH2Cl2) N 45 OCHF As shown in Scheme II, the ring of compound 3 is (11 (S)) selectively opened by contacting it with an organometallic FHCO reagent to provide a compound of Formula 1. Examples of OCH organometallic reagents include, but are not limited to, those 50 of the formula MX, wherein M' of the formula MX is Al, le OCH Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, Cu or is of the formula YY CdZ, BaZ, Mgz, Zinz, AIZ Mnz, Inz, CuZ, Ti(OR), Prot O O N N Z", or Ti(OR), wherein Z is Cl, Br, I, aryl, aralkyl, or 55 heterocycle, wherein R is defined herein. (13 (S))

The sulfur-oxygen bond of the compound of Formula 1 is -- then cleaved by contacting it with a compound of formula MY to provide the desired sulfinamide or sulfoxide of R Formula 2. MY can be the same or different from MZ: M is 60 R NHSOR a metal such as Al, Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, Cu or is of the formula CdZ, BaZ, Mg2, Zinz, AIZ, Mnz. InZ. or CuZ, Ti(OR)2, or Ti(OR), wherein Z is Cl, Br, I, aryl, R OH R" aralkyl, or heterocycle, wherein R is defined herein. 65 Depending on the actual compound of formula MY, this (29) final reaction of Scheme II can provide a variety of different

US 7,256.297 B2 29 30

-continued -continued CH3 le OC5H1 5

Prot YY5 9 N N

(24 (S)) 10

--

R YOH

(29) In each of schemes III-VI, Mand Mare as defined herein, and Prot is a protecting group. Suitable protecting groups are known in the art and include, but are not limited to, —CHOCH, —CHOCHOCH, alkyl sulfonyl, and aryl sulfonyl. 25 The reagents used in each of these schemes are commer cially available or readily prepared. For example, the ben Zimidazole metal conjugates used in the first step of each of schemes III-VI (i.e., compounds 14, 18, 22 and 18) can be prepared by methods known in the art. See, e.g., Abarbri, M., 30 et al., Tetrahedron Lett. (1999) 40:7449-7453 and Abarbri, M., et al., J. Org. Chem. (2000) 65:4618-4634. The synthesis of protected benzimidazoles is also well known. See, e.g., Sih, J. C. et al., J. Med. Chem. (1991) 34:1049-1062 and Singh, M. P. et al., Heterocycles (1993) 36:971-985. The 35 pyridinyl metal conjugates used in the second step of cach of the schemes (i.e., compounds 12, 16, 20, and 23) are also readily prepared using well-known methods. See, e.g., Baldenius, K.-U. and Kagan, H. B., Tetrahedron: Asym. (1990) 1:597-610. 40 5. EXAMPLES Certain embodiments of the invention are illustrated by the following non-limiting examples. 45 5.1. Example 1 Asymmetric Synthesis of a Sulfinamide via 1.2.3-oxathiazolidine-S-oxide 50 Examples of the general approach shown in Scheme II are described below, and can be understood with reference to Schemes VII-XII:

Scheme VII 55 SOCI

60 (8)

65 (31) (30) US 7,256.297 B2 32

SOCI SOCI

s

... II iOH 10 OH He

(34)

15

25

30

35

40

45

(37)

55

HN i 60

III IOH (8) (8)

65 (35) (38) US 7,256.297 B2 33 34

-continued

SOCI

s 10 i III iOH He (8)

(34) 15 (41)

SOCI

25

OH ---

30 (30)

35

40

45

50

55

60

65 US 7,256.297 B2 35 36

-continued -continued

10

15 (46) (45)

25 HN -k NH i

OH (8) 30

(38)

35 N H

SOCI 40

s 45 Preparation of (1R,2S)-1-amino-2-indanol-N-2,4,6-mesi II IOH tylsulfonamide (31): To a 2 L ml three neck round-bottomed flask equipped with an overhead stirrer and temperature probe, was charged NaHCOs (42.2g, 502 mmol), followed (34) by 200 mL of water and the mixture was stirred for 15 min. 50 EtOAc (500 mL), THF (100 mL), and aminoindanol (30) (50 g, 336 mmol) were added and the slurry was mixed for 5 minutes. 2-Mesitylenesulfonyl chloride (70.4g, 322 mmol) was added in one portion, the reaction mixture was stirred vigorously for 5-6 hours, and the reaction was monitored by 55 TLC for the disappearance of 2-mesitylenesulfonyl chloride. Stirring was stopped and the phases were allowed to sepa rate. The organic phase was washed with water (200 mL), 1.5 M HCl (75 mL) and water (200 mL). Evaporation of the organic solvent to dryness provided a solid product which 60 was treated with heptane (400 mL) and the mixture was stirred for 2 hours. The resulting slurry was filtered and the wet cake dried under reduced pressure to give 104 g (93%) III IOH of the title product. "H NMR (300 MHz, CDC1): 8 2.30 (s, 3H), 2.68 (s, 6H), 2.81-3.04 (m, 3H), 4.22-4.32 (m. 1H), 65 4.48-4.58 (m. 1H), 5.58-5.61 (d. J=9.5 Hz, 1H) 6.95-7.24 (41) (m, 6H). 'C NMR (CDC1): 8 21.3, 23.3, 39.6, 61.3, 73.2, 124.9, 125.6, 127.4, 128.7, 132.3, 134.1, 139.7, 139.8, US 7,256.297 B2 37 38 140.0, and 142.8. Alal. Calcd for C.H. NOS: C, 65.23; H, tored by TLC for disappearance of starting material, the 6.39: N, 4.23; O, 14.48; 5, 9.68. Found: C, 65.36; H, 6.40: reaction mixture was cooled to -5° C. and quenched with N, 4.08; S, 9.70. aqueous NaHCOs (40 mL), diluted with EtOAc (100 mL) Preparation of (2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3, and warmed to room temperature. The organic layer was 3a,8.8a-tetrahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene washed with brine (100 mL) and concentrated to dryness. 2-oxide (32) from (1R,2S)-aminoindanol mesitylene sul The residue was added heptane (100 mL), stirred for 2 hours, fonamide (31): To a 1 L three-necked flask equipped with a and filtered to give a white or off white solid product (11.0 mechanical stirrer, an argon inlet, a thermometer probe and g, 95.5%) with >97% de (the crude product was used rubber septum, was charged (1R,2S)-aminoindanol mesi directly in the next step). Crystallization from EtOAc/ tylene sulfonamide (31 g, 93.7 mmol), THF (50 mL) and the 10 heptane furnished diastereomeric pure product (>99% de. reaction mixture was cooled to -45° C. Thionyl chloride minor diastereomer not detected). (15.2 g, 128 mmol) was added slowly via Syringe in one Preparation of (2R,4S.5R)-3-(4-toluenesulfonyl)-3.3a.8, portion, followed by slow addition of collidine (32 g, 264 8a-tetrahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene 2-OX mmol) in THF (250 mL) for 6 hours. The reaction was ide (46) from (1S,2R)-1-amino-2-indanol-N-4-toluene quenched with aqueous NaHCO (100 mL), diluted with 15 sulfonamide (41): The same procedure described above was EtOAc (100 mL) and warmed to room temperature. The used to provide the title product with same result. "H NMR organic layer was washed with brine (100 mL), dried with (CDC1): 82.46 (s.3H), 3.31 (s. 2H), 5.02-5.04 (d. J=5.0 Hz, NaSO and concentrated to dryness. The residue was added 1H), 5.77-5.82 (m, 1H), 7.22-7.42 (m, 5H), 7.96-8.04 (m, heptane (150 mL), stirred for 2 hours, and filtered to give a 3H). 'C NMR(CDC1): 8 22.0, 36.2, 65.1, 90.6, 125.2, white or off white solid product with 85% de. Crystallization 127.0, 128.9, 129.8, 130.2, 135.5, 137.9, 139.2, 145.5. Anal from EtOAc/heptane provided a white solid product. The CHNOS, Cal: C, 55.0; H, 4.33: N, 4.01; S, 18.35. mother liquor was concentrated, and a second crop of Found: C, 55.11; H, 4.35; N, 4.00; S, 18.4. crystals was obtained. This process was repeated two times Preparation of (S)-2-Methyl-2-propylsulfinic acid (1R, to give a total yield of 28 g (78%) of (2R,4R,5S)-3-(2,4,6- 2S)-1-(2.4.6-mesitylsulfonylamino)-indan-2-yl ester (33) mesitylsulfonyl)-3.3a,8.8a-tetrahydro-1-oza-2-thia-3-aza 25 from (2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3.3a,8.8a-tet cyclopentaalindene 2-oxide (32) with >99% de. rahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene 2Oxide Preparation of (2S,4S.5R)-3-(2,4,6-mesitylsulfonyl)-3.3a, (32): In a 100 mL two-necked, round-bottomed flask 8.8a-tetrahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene equipped with a magnetic stir bar, rubber septum, and argon 2-oxide (36) from (1S, 2R)-1-amino-2-indanol-N-2,4,6- inlet was placed (2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3.3a, mesitylsulfonamide (35): The same procedure described 30 8.8a-tetrahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene above was used to provide the product with 76% yield and 2-oxide (32) (2.2g, 5.8 mmol) dissolved in THF (20 mL) >99% de. "H NMR (CDC1): 8 2.41 (s, 3H), 2.77 (s, 6H), and the mixture was cooled to -10°C. A solution of t-butyl 3.40-3.66 (m, 2H), 5.57 (d. J=6.4 Hz, 1H), 5.86-5.91 (m, magnesium chloride (10.8 mL, 1.0 M) in THF was added 1H), 6.63 (d. J=8.1 Hz, 1H), 7.08-7.34 (m, 5H). 'C NMR dropwise via Syringe for 1 hour and the reaction was allowed (CDC1): 8 21.5, 23.4, 39.6, 66.6, 96.0, 125.0, 125.8, 128.1, 35 to warm to room temperature with stirring. After 2 hours, as 129.8, 132.8, 138.8, 141.2, 145.1. Anal. CHNOS, Cal: monitored by TLC for the disappearance of the starting C, 57.27; H, 5.07; N, 3.71; S, 16.99. Found: C, 57.45; H, material, the reaction mixture was cooled to 0°C. quenched 5.14: N, 3.76; S, 16.93. with aqueous NaHCO (10 mL), and diluted with EtOAc (20 Preparation of aminoindanol 4-toluene sulfonamide (1R, mL). The aqueous phase was extracted with EtOAc (10 mL). 2R.3S)-1,2,3-oxathiazolidine-S-oxide (39) from (1R,2S)-1- 40 The combined organic phases were washed with brine (20 amino-2-indanol-N-4-toluenesulfonamide (38) or aminoin mL), dried with NaSO and concentrated to afford a crys danol 4-toluene sulfonamide (1S, 2S, 3R)-1,2,3- talline product (2.45 g, 96.5%) with >99% de (minor dias oxathiazolidine-S-oxide (42) from (1S,2R)-1-amino-2- tereomer not detected). indanol-N-4-toluenesulfonamide (41): The same procedure Preparation of (R)-2-Methyl-2-propylsulfinic acid (1S, described above was used to provide the title compound 45 2R)-1-(2,4,6-mesltylsulfonylamino)-indan-2-yl ester (37) quantitatively with 82% de. Crystallization from heptane/ from (2S,4S.5R)-3-(2,4,6-mesitylsulfonyl)-3.3a,8.8a-tet EtOAc furnished the diastereomeric pure product with rahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene 2-oxide >99% de (minor diastereomere not detected) and 65% yield. (36): The same procedure described above was used. The "H NMR(CDC1): 8 2.51 (s, 3H), 3.32-3.62 (m, 2H), 5.38 result provided 95% yield and >99% de. "H NMR(CDC1): 5.52 (m, 2H), 7.81-7.89 (m, 6H), 7.81-7.89 (m, 2H). 'C 50 & 1.07 (s, 9H), 2.32 (s, 3H), 2.71 (s, 6H), 3.06 (s. 2H), MNR (CDC1): 8 22.0, 39.7, 67.1, 93.3, 125.6, 126.0, 127.8, 4.75-4.85 (m, 2H), 5.64 (d. J=9.3 Hz, 1H), 6.99 (s, 1H), 128.1, 130.0, 130.6, 135.9, 138.2, 138.6, 145.6. Anal: 7.17-7.28 (m, 5H). C NMR (CDC1): 8 21.1, 21.8, 37.8, CHNS, Cal: C, 55.00; H, 4.33: N, 4.01; S, 18.35. 58.1, 60.5, 82.7, 124.8, 124.9, 127.8, 128.5, 132.3, 134.6, Found: C, 55.09: H, 4.37; N, 3.92; S, 18.39. 137.8, 139.6, 140.3, 142.6. Anal. CHNOS: Cal. C. Preparation of (2S,4R,5S)-3-(4-toluenesulfonyl)-3.3a,8. 55 60.66; H, 6.71: N, 3.22; S, 14.72. Found: C, 60.75; H, 6.72: 8a-tetrahydro-1-Oxa-2-thia-3-aza-cyclopentaalindene 2-OX N, 3.15; S, 14.65. ide (44) from (1R, 2S)-1-amino-2-indanol-N-4-toluene Preparation of (S)-2-Methyl-2-propylsulfinic acid (1R, sulfonamide (38): A 250 mL three-necked flask equipped 2S)-1-(4-toluenesulfonyl-amino)-indan-2-yl ester (40) from with a mechanical stirrer, an argon inlet, a thermometer (2R,4R,5S)-3-(4-toluenesulfonyl)-3.3a,8.8a-tetrahydro-1- probe and rubber septum, was charged (1R,2S)-1-amino 60 oxa-2-thia-3-aza-cyclopentaalindene 2-oxide (39) and (R)- 2-indanol-N-4-toluenesulfonamide (10.0 g, 33.0 mmol), tert-butyl (1S, 2R) aminoindanol 4-toluene sulfonamide THF (30 mL) and the reaction mixture was cooled to -45° sulfinate (43) from aminoindanol 4-toluene sulfonamide C. Thionyl chloride (5.9 g, 49.6 mmol) was added slowly via (1S,2S,3R)-1,2,3-oxathiazolidine-S-oxide (42): The same syringe in one portion, followed by slow addition of 2,6-di procedure described above was used to provide the title t-butyl pyridine (15.8 g., 80.0 mmol) in THF (100 mL) for 65 product with 96% yield and >99% de. "H NMR (CDC1): 8 1-2 hours, and the reaction mixture was allowed to warm to 1.12 (s, 9H), 2.48 (s.3H), 2.95-3.14 (m, 2H), 4.64-4.70 (m, room temperature with stirring. After 6-8 hours, as moni 1H), 4.76-4.84 (m. 1H), 5.76 (d. 9.2 Hz, 1H), 7.16-7.50 (m, US 7,256.297 B2 39 40 6H), 7.94-7.97 (m, 2H). 'C NMR (CDC1): 8 21.7, 38.0, de was measured by "H NMR). H NMR (CDC1): 8 1.40 (s, 58.2, 60.6, 83.1, 124.9, 124.995, 127.8, 128.6, 130.0, 137.5, 9H), 2.34 (s, 3H), 2.74 (s, 6H), 3.06-3.08 (s. 2H), 4.77-4.90 140.1, 143.8. Anal: CHNOS. Cal: C, 58.94; H, 6.18: (m. 2H), 5.65 (d. J=10 Hz), 7.02 (s, 1H), 727-7.37 (m, 5H). N, 3.44; S, 15.74. Found: C, 59.10; H, 6.22: N, 3.35; S, 'C NMR (CDC1): 8 212, 21.8 37.8, 58.1, 60.5, 82.7, 15.79. 124.8, 124.9, 127.8, 128.5, 132.3, 134.6, 137.6, 139.6, Preparation of (R)-2-Methyl-2-propylsulfinic acid (1R, 140.5, 142.6. 2S)-1-(4-toluenesulfonylamino)-indan-2-yl ester (45) from Preparation of (R)-t-butylsulfinamide (8(R): LR)-TBSA) (2S,4R,5S)-3-(4-toluenesulfonyl)-3.3a,8.8a-tetrahydro-1- from (S)-tert-Butyl (1R,2S)-aminoindanol mesitylene sul oxa-2-thia-3-aza-cyclopentaalindene 2-oxide (44): In a 100 fonamide sulfinate (33): A 250 mL three-necked round mL two-necked, round-bottomed flask equipped with a 10 bottomed flask equipped with a mechanical stirrer and an magnetic stir bar, rubber septum, and argon inlet was ammonia condenser at about -78°C. was charged with 50 placed(2S,4R,5S)-3-(4-toluenesulfonyl)-3.3a,8.8a-tetrahy mL of liquid ammonia under Ar atmosphere. After the dro-1-Oxa-2-thia-3-aza-cyclopentaalindene 2-oxide (4.5 g. addition of a few crystals of Fe(NO), lithium wire (0.25 g, 12.9 mmol) dissolved in THF (30 mL) and the mixture was 35 mmol) was added portion-wise in a controlled manner cooled to 0°C. A solution of t-butyl magnesium chloride (25 and the internal temperature was kept around -45° C. When mL, 1.0 M) in THF was added dropwise via syringe for 30 15 all the lithium was added and a gray Suspension was formed, minutes with stirring. After 3-4 hours, as monitored by TLC the reaction mixture was cooled to -78°C. and a solution of for the disappearance of the starting material, the reaction (S)-t-butyl (1R,2S)-aminoindanol mesitylene sulfonamide was quenched with aqueous NaHCO (20 mL), and diluted sulfinate ester (5 g, 11.5 mmol) in THF (15 mL) was added with EtOAc (50 mL). The aqueous phase was extracted with slowly over a course of 45 min. Once the addition was EtOAc (20 mL) and the combined organic phases were complete, the mixture was stirred for additional 30-45 min. washed with brine (40 mL), dried with NaSO and con before NHCl (2.8 g) was added. The cold bath was centrated to afford a crystalline product (5.0 g, 95%) with removed, and stirring continued until the mixture reached >99% de (minor diastereomer not detected). H NMR ambient temperature. The remaining volatile material was (CDC1): 8 1.12 (s, 9H), 2.45 (s, 3H), 3.08-3.26 (m, 2H), removed under reduced pressure. To the remaining residue 4.84-4.88 (m, 1H), 4.94-4.97 (m. 1H), 5.32 (d. J=10.1 Hz), 25 was added 5 mL water and stirred. EtOAc (50 mL) was 7.06-7.35 (m, 6H), 7.83-7.86 (m, 2H). ''C NMR (CDC1): added to the mixture and stirred. After separation of the 8 21.7, 21.9, 38.6, 58.3, 60.8, 81.8, 124.1, 125.2, 127.3, phases, the organic phase was washed with brine (5 mLX2). 127.5, 128.9, 130.0, 138.1, 138.5, 139.2, 143.9. After removal of the organic solvent, the residue was added Preparation of (S)-t-butyl (1R,2S) aminoindanol mesity water (40 mL) and stirred for 1 hour. The slurry was filtered lene sulfonamide sulfinate (33) (one pot procedure): A 50 30 and the wet cake was washed with water (10 mL). The mL three-necked flask equipped with a mechanical stirrer, an aqueous filtrate was then saturated with NaCl and extracted argon inlet, a thermometer probe and rubber septum, was with EtOAc (20 mLX3). Removal of the organic solvent charged (1R,2S)-aminoindanol mesitylene Sulfonamide afforded (R)-t-butylsulfinamide (0.75 g, 70%) with 97% ee. (1.22 g, 3.2 mmol), THF (3 mL) and the reaction mixture (HPLC, Chiralpak AS column, 90:10 hexane/ethanol; 1.2 was cooled to -45° C. Thionyl chloride (0.58 g, 4.9 mmol) mL/min, 222 nmi; (R)-TBSA r-G.6 min. (S)-TBSA, r9.4 was added slowly via Syringe in one portion, followed by 35 min.). "H NMR (CDC1): 81.18 (s.9H), 3.82 (br, s, 2H). 'C slow addition of collidine (1.19 g, 9.8 mmol) in THF (10 NMR(CDCIJ): & 22.1, 55.3. mL) for 3-4 hours, and the reaction was monitored by TLC. Preparation of (R)-2-Methyl-2-propylsulfinic acid (1S, The reaction mixture was warmed to -5° C. -10° C. and 2R)-1-(2,4,6-mesitylsulfonylamino)-indan-2-yl ester (37) or stirred for 5 min. The collidine-HCl salt was filtered and the from (R)-2-Methyl-2-propylsulfinic acid (1R,2S)-1-(4-tolu cake washed with THF (4 mL). The filtrate was cooled to 40 enesulfonylamino)-indan-2-yl ester (45): The same proce -78° C. and thBuMgC1 (6.4 mL, 1.0 M) in THF was added dure described above was used to provide the title products slowly. After 4-5 hours, as monitored by TLC for the with 98% ee and 73% yield or 98% ee and 72% yield, disappearance of the starting material, aqueous NaHCO (10 respectively. mL) was added to quench the reaction, diluted with EtOAc (15 mL) and the mixture was allowed to warm to room 45 5.2. Example 2 temperature The organic phase was washed with brine, 10% NaCl and dried (NaSO). Removal of the solvent afforded Sulfanamide Synthesis via (1S,2R)-1-(n-mesitylene a viscous oil that was added EtOAc (3 mL) and heptane (10 Sulfonyl)amino-1-phenyl-2-propanol mL) and stirred for 30 minutes. The crystalline precipitate formed was filtered and washed with heptane and dried to One method of preparing Sulfinamides is represented by afford the title compound (1.2g, 75%) with >95% de. (The Scheme XIII, below:

OH OH SOCI

NHHCI He-EtN/CHCl2 V

(48) (49) 2,4,6-collidine THF-45 C. US 7,256.297 B2 41 42

-continued OG

Ovs. GN(CH (CH3)3

NH V BuMgCl /V THF-78 C. O O

(51) NHLi/NH -45 C.

OH

NH V MVS -- HN 16NCH), O O (8)

(49)

30 Preparation of (1S,2R)-N-(2-hydroxy-1-phenyl-propyl)- 14.18 mmol) in THF (10 mL) for 2-3 hours, and the reaction 2.4.6-mesitylsulfonamide (49): (1S,2R)-1-amino-1-phenyl was monitored by TLC for the disappearance of starting 2-propanol (48) (2.0 g, 10.6 mmol) was charged into a 100 material. The reaction was quenched with Saturated aqueous mL three neck round-bottomed flask equipped with an 35 NaHCO (10 mL), diluted with EtOAc (20 mL) and the overhead stirrer and temperature probe, followed by meth mixture was warmed to room temperature. The organic layer ylene chloride (20 mL) and the mixture was cooled to 0°C. was washed with brine (10 mL) and concentrated to dryness. and stirred for 15 minutes. 2-Mesitylenesulfonyl chloride The residue was added heptane (20 mL), stirred for 2 hours, (2.2g, 10.1 mmol) was added in one portion and the slurry and filtered to give a white or off white solid product with was mixed for 5 minutes. Triethylamine (2.7 g. 26.7 mmol) 40 94% de. Crystallization from MTBE furnished diastereo was added in 2 hours with stirring and the reaction was meric pure product (1.9 g, 88.5%) with >99% de (minor monitored by TLC for the disappearance of 2-mesitylene diastereomer not detected by NMR). "H NMR (CDC1): 8 sulfonyl chloride. The reaction was quenched with saturated 1.14 (d. J=6.59 Hz, 3H), 2.16 (s, 3H), 2.52 (s, 6H). 4.87 (d. aqueous NaHCO (20 mL) and diluted with EtOAc (20 mL). 45 J=6.72 Hz, 1H), 5.16 (p, J=6.59, 1H), 6.70 (s. 2H), 7.08-7.13 The organic phase was washed with water (20 mL), 1.0 M (m, 5H). ''C NMR (CDC1): 8 18.07, 21.06, 23.00, 65.34, HCl (10 mL), water (20 mL) and dried over NaSO. Evapo 87.64, 128.20, 128.28, 131.51, 132.11, 132.93. 140.59, ration of the organic solvent to dryness provided the title 144.23. Anal: C18H21NO4S2. Cal: C, 56.97; H, 5.58: N, product in 95% yield (3.3 g). "H NMR (CDC1): 8 1.02 (d. 3.69; S, 16.90. Found: C, 57.16; H, 5.62: N, 3.62; S, 16.94. 50 (S)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2- J=6.35 Hz, 3H), 2.14 (d. J=5.49 HZ, 1H), 2.21 (s, 3H), 2.49 phenyl-2-(2,4,6-mesitylsulfonylamino)-ethyl ester (51): In a (s, 6H), 4.07-4.11 (m. 1H), 4.15-4.18 (m, 1H), 5.70 (d. 50 mL two-necked, round-bottomed flask equipped with a J=7.21 Hz, 1H), 6.76 (s. 2H), 6.99-7.15 (m, 5H). ''C NMR magnetic stir bar, rubber septum, and argon inlet was placed (CDC1): 8 19.5, 21.1, 23.1, 63.0, 70.4, 127.9, 128.3, 132.0, (2S, 4S, 5R)-5-methyl-4-phenyl-3-(2,4,6-mesitylsulfonyl)- 134.3, 136.7, 139.0, 142.3. Anal: C18H23NO3S. Cal: C, 55 1.2.3oxathiazolidine 2-oxide (50) (0.58 g, 1.53 mmol) 64.84; H, 6.95; N, 4.20, S, 9.62. Found: C, 65.19; H, 7.04; dissolved in THF (1.0 mL) and the mixture was cooled to N, 4.18; S, 9.71. -78°C. A solution of t-butyl magnesium chloride (3.1 mL, Preparation of (2S, 4S, 5R)-5-methyl-4-phenyl-3-(2,4,6- 1.0 M) in THF was added dropwise via syringe for 30 mesitylsulfonyl)-1.2.3oxathiazolidine 2-oxide (50): A 50 minutes with stirring. After 1-2 hours, as monitored by TLC 60 for the disappearance of the starting material, the reaction mL three-necked flask equipped with a mechanical stirrer, an was quenched with Saturated aqueous NaHCO (5 mL), and argon inlet, a thermometer probe and rubber septum, was diluted with EtOAc (5 mL). The aqueous phase was (1S, 2R)-N-(2-hydroxy-1-phenyl-propyl)-2,4,6-mesitylsul extracted with EtOAc (4 mL) and the combined organic fonamide (49) (1.89 g, 5.67 mmol), THF (5 mL) and the phases were washed with brine (5 mL), dried with (NaSO) reaction mixture was cooled to -45° C. Thionyl chloride 65 and concentrated to afford a crystalline product (0.65 g, (1.01 g, 8.50 mmol) was added slowly via syringe in one 97%) with >99% de (minor diasteriomer not detected). H portion, followed by slow addition of 2,4,6-collidine (2.10 g, NMR (CDC1): 8 1.080 (d. J=6.47 Hz, 3H), 1.1749 (s.9H), US 7,256.297 B2 43 44 2.163 (s.3H), 2.485 (s, 6H), 4.394 (dd, J1=8.98 Hz, J2=2.32 stirring continued until the mixture reached ambient tem HZ, 1H), 4.675 (dq, J1=2.32 Hz, J2=6.53 Hz, 1H), 6.61-6.67 perature. The remaining Volatile material was removed (m. 2H), 6.96-7.09 (m, 5H). ''C NMR (CDC1): 8 19.10, under reduced pressure. To the remaining residue was added 20.90, 21.80, 22.98, 57.85, 61.10, 81.86, 127.58, 128.80, 131.61, 134.98, 135.10, 138.50, 141.55. 2 mL water and stirred. EtOAc (5 mL) was added to the Preparation of (S)-t-butylsulfinamide ((S)8) from (S)-2- mixture and stirred. After separation of the phases, the Methyl-2-propylsulfinic acid (1S, 2R)-1-methyl-2-phenyl organic phase was washed with brine (2 mLX2). After 2-(2,4,6-mesitylsulfonylamino)-ethyl ester (51): A 50 mL removal of the organic solvent, the residue was purified by three-necked round-bottomed flask equipped with a mag chromatography eluted with EtOAc to afforded (S)-t-butyl netic stir bar and an ammonia condenser was charged with 10 sulfinamide (0.125 g, 99%) with 99% ee. (HPLC, Chiralpak 30 mL of liquid ammonia under Ar atmosphere. After the AS column, 90:10 hexane/ethanol; 1.2 mL/min, 222 nm, addition of a few crystals of Fe(NO), lithium wire (0.05 g, (R)-TBSA r-6.6 min: (S)-TBSA, r-9.4 min.). H NMR 7.1 mmol) was added in a controlled manner and the internal (CDC1): 8 1.18 (s, 9H), 3.82 (br, s, 2H). ''C NMR(CDC1): temperature was kept around -45° C. When all the lithium 15 & 22.1, 55.3. was added and a gray Suspension was formed, the reaction mixture was cooled to -78° C. and a solution of (S)-2- 5.3. Example 3 methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2-phenyl-2- (2.4.6-mesitylsulfonylamino)-ethyl ester (51) (0.45 g, 1.03 Sulfinamide Synthesis via (1S,2R)-Norephedrine mmol) in THF (1 mL) was added slowly over a course of 20 4-Toluene Sulfonamide minutes. Once the addition was complete, the mixture was warmed to -45° C. and stirred for 1 hour, followed by Another method of preparing Sulfinamides is represented addition of NHCl (0.5 g). The cold bath was removed, and by Scheme XIV, below:

Scheme XIV

SOCI wOH EtN/CHCl2 OH -- --- “NH V 'NH, //V \, (52) (53) COCl. 2,4,6-collidine THF-45 C. Oe S-C(CH3), /e wO BuMgCl wO\ OO -e- S' THF-78 C. 'NH in, G /MV \O /MV \, (55) NHLi/NH (54) -45 C.

wOH e

'', -- HN11SN G. C(CH) NH US 7,256.297 B2 45 46 Preparation of (1S,2R)-N-(1-hydroxy-2-methyl-1 phenyl washed with brine (40 mL), dried with (Na2SO) and ethyl)-4-toluene sulfonamide (53): To a 250 mL threeneck concentrated to afford a crystalline product (5.2g, 99%) with round-bottomed flask equipped with an overhead stirrer and 97% de. temperature probe, was charged (1S, 2R)-norephedrine (S)-2-Methyl-2-propylsulfinic acid (1R,2S)-1-phenyl-2- (10.0 g. 66.1 mmol), followed by tosyl chloride (12.1 g, 63.6 (4-toluenesulfonylamino-propyl ester was prepared by fol mmol) and the mixture was cooled to 0°C. and stirred for lowing the same method with 98% yield and 97% de. "H 15 minutes. Then EtN was added in 2 hours with stirring NMR (CDC1): 8 0.981 (d. J=6.84 Hz, 3H), 1.251 (s, 9H), and the reaction was monitored by TLC. The reaction was 2.428 (s.3H), 3.56-3.675 (m, 1H), 4.956 (d. J–2.32 Hz, 1H), quenched with saturated aqueous NaHCO (50 mL). The 5.841 (d. J=9.77 Hz, 1H), 7.073-7.105 (m. 2H), 7.270-7.350 organic phase was washed with water (50 mL), 1.0 M HCl 10 (m, 5H), 7.85-7.879 (m, 2H). 'C NMR (CDC1): & 14.88, 21.67, 21.90, 54.57, 58.34, 84.82, 125.98, 127.31, 128.36, (25 mL), water (50 mL) and dried over NaSO. Evaporation 128.66, 129.86, 137.37, 138.48, 143.46. of the organic solvent to dryness provided a oily crude Preparation of (R)-t-butylsulfinamide ((R)-TBSA) from product that was crystallized from MTBE/hexane to give the (R)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-phenyl-2-(4- title product (18.5 g) with 90% yield. 15 toluenesulfonylamino)-propyl ester (55): A 100 mL three (1R,2S)-Norephedrine 4-toluene sulfonamide was pre necked round-bottomed flask equipped with a magnetic stir pared by following the same method with 91% yield. "H bar and an ammonia condenser was charged with 50 mL of NMR (CDC1): 8 0.814 (d. J=6.83 Hz, 3H), 2.40 (s, 3H), liquid ammonia under Ar Atmosphere. After the addition of 3.116 (d. J=4.76 Hz, 1H), 3.42-3.52 (m. 1H), 4.786-4.812 a few crystals of Fe(NO), lithium wire (0.3 g, 42.8 mmol) (m. 1H), 5.138 (d. J=8.67 Hz, 1H), 7.200-7.316 (m, 7H), was added in a controlled manner and the internal tempera 7.767 (d. J=8.30 Hz, 2H). CNMR(CDC1): & 1449, 55.16, ture was kept around -45°C. when all the lithium was added 75.85, 126.19, 127.16, 127.69, 128.41, 129.90, 137.84, and a gray Suspension was formed, the reaction mixture was 140.48, 143.60. cooled to -78° C. and a solution of (S)-t-butyl (1S,2R)- Preparation of (2R, 4R, 5 S)-4-methyl-5-phenyl-3-(4- norephedrine sulfinate (2.6 g. 6.3 mmol) in THF (6 mL) was toluenesulfonyl)-1.2.3oxathiazolidine 2-oxide (54): A 100 25 added slowly over a course of 40 minutes. Once the addition mL three-necked flask equipped with a magnetic stir bar, an was complete, as the reaction was monitored by TLC for the argon inlet, a thermometer probe and rubber septum, was disappearance of the starting material, the mixture was charged (1S, 2R)-N-(1-hydroxy-2-methyl-phenyl-ethyl)-4- added NHCl (4.0 g). The cold bath was removed, and stirring continued until the mixture reached ambient tem toluenesulfonamide (53) (5.2g, 17.04 mmol), THF (15 mL) 30 perature. The remaining Volatile material was removed and the reaction mixture was cooled to -45° C. Thionyl under reduced pressure. To the remaining residue was added chloride (3.04 g. 25.5 mmol) was added slowly via syringe 5 mL of water and stirred. EtOAc (50 mL) was added to the in one portion, followed by slow addition of 2.4.6-collidine mixture and stirred. After separation of the phases, the (6.2g, 51.2 mmol) in THF (30 mL) for 2-3 hours, and the organic phase was washed with brine (6 mLx2). After reaction was monitored by TLC for the disappearance of 35 removal of the organic solvent, the residue was purified with starting material. The reaction was quenched by addition of chromatography eluted with EtOAc to afforded (R)-t-butyl NaHCO (5.0 g) and saturated aqueous NaHCO (20 mL), sulfinamide (0.65 g, 85%) with 96% ee. diluted with EtOAc (40 mL) and the mixture was warmed to Preparation of (S)-t-butyl sulfinamide from (S)-2-Methyl room temperature. The organic layer was washed with brine 2-propylsulfinic acid (1R,2S)-1-phenyl-2-(4-toluenesulfo (50 mL), dried over NaSO and concentrated to dryness. 40 nylamino)-propyl ester: The same procedure described The residue was added heptane (50 mL), staged for 1 hour, above was followed, an furnished the title product in 86% and filtered to give a white or off white solid product (5.6 g. yield and 96% ee. (HPLC, Chiralpak AS column, 90:10 94%) with 97% de. The product was used directly in the next hexane/ethanol; 1.2 mL/min, 222 nmi; (R)-TBSA ré.6 min: step reaction. Diastereomerically pure compound was (S)-TBSA, r-9.4 min.). "H NMR(CDC1): 8 1.18 (s, 9H), obtained by crystallization from MTBE. 45 (2S, 4S, 5R)-3-Tosyl-4-methyl-5-phenyl-2-oxo-1,2,3-ox 3.82 (br, s, 2H). ''C NMR (CDC1): 8 22.1, 55.3. athiazolidine was prepared by following the same method 5.4. Example 4 with 93% yield and 97% de. "H NMR (CDC1): 8 0.868 (d. J=6.97 Hz, 3H), 2.545 (s, 3H), 4.210 (p, J=6.48 Hz, 1H), Preparation of Enantiomerically Pure Sulfoxides 5.572 (d. J=5.98 Hz, 1H), 7.284-7.388 (m, 7H), 7.864-7.892 50 (m. 2H). ''C NMR (CDC1): 8 16.59, 21.48, 57.12, 92.14, Stereomerically pure (e.g., enantiomerically pure) sulfox 126.39, 127.68, 128.86, 129.16, 130.35, 133.41 136.62, 145.34. ides can be readily prepared using methods of the invention. (R)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-phenyl-2- Specific methods are shown below in schemes XV and XVI: (4-toluenesulfonylamino)-propyl ester (55): In a 100 mL 55 two-necked, round-bottomed flask equipped with a magnetic Scheme XV stir bar, rubber septum, and argon inlet was placed (2R, 4R, 5S)-4-methyl-5-phenyl-3-(4-toluenesulfonyl)-1,2,3ox R3 athiazolidine 2-oxide (54) (4.5 g, 12.8 mmol) dissolved in OFSFO THF (30.0 mL) and the mixture was cooled to -78° C. A 60 solution of t-butyl magnesium chloride (25 mL, 1.0 M) in NH THF was added dropwise via syringe for 30 minutes with stirring. After 1-2 hours as monitored by TLC for the MY disappearance of the starting material, the reaction was OS-X He quenched with aqueous NaHCO (30 mL), and diluted with 65 EtOAc (40 mL). The aqueous phase was extracted with o EtOAc (20 mL) and the combined organic phases were US 7,256.297 B2 4 8

-continued R3 OE i EO -k NH

X Y OH -- ns-1 10 Preparation of (R)-t-Butyl isobutyl sulfoxide: The same /a, procedure was followed using (R)-tert-butyl (1S,2R)-ami Y = alkyl (linear or branched or cyclic), aryl, noindanol mesitylene Sulfonamide Sulfinate, and afforded a hetero atom containing alkyl or aryl group 90% yield. M = MgHal, or Li; Hal = halogen "H NMR (CDC1): 8 1.24 (s, 9H), 1,086-1.126 (m, 6H), 15 2.20-2.30 (m, 2H), 2.38–2.45 (m, 1H). ''C NMR (CDC1): 8 21.78, 23.06, 23.49, 24.12, 52.63, 55.00, Anal: Cal: C, 59.20; H, 11.18; S, 19.76. Found: C, 59.39; H, 11.36; S, Scheme XVI 1965. O O \/S A NH Men S -k --- O 25 GNs 6 Preparation of (S)-t-butyl methyl sulfoxide from (2S,4S, O 5R)-3-(2,4,6-mesitylsulfonyl)-3.3a,8.8a-tetrahydro-1-oxa 2-thia-3-aza-cyclopentaalindene 2-oxide (one pot proce Me n S -k -- dure): A solution of (2S,4S.5R)-3-(2.4.6-mesitylsulfonyl)-3, o 3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopentaalindene O G 2-oxide (1.44 g, 3.82 mmol) in THF at -15°C. was slowly O O added to t-BuMgCl (4.0 mL, 1.0M) in THF, and the reaction 35 mixture was stirred (1–2 hours) until the reaction complete 1\/ as monitored by TLC. Methyl magnesium bromide (4.4 mL, NH 1.0 M) in THF was then added, the reaction mixture was warmed to room temperature and stirred for 1-2 hours. The reaction was monitored by TLC. After the reaction mixture OH 40 was cooled to 0°C., the reaction was quenched by addition of saturated aq. NHCl (5 mL), stirred and diluted with EtOAc (5 mL). The aqueous phase was extracted with EtOAc (5 mLx2) and the organic solvent was evaporated. The residue was purified on silica gel eluted with EtOAc/ The following can be understood with reference to the 45 MeOH (8:2) to give the title product (0.38 g, 83%). schemes shown above. Preparation of S)-t-butyl methyl sulfoxide from (S)-t- Butyl (1S,2R)-norephedrine sulfinate: ATHF (2 mL) solu tion of (S)-t-butyl (1S, 2R)-norephedrine sulfinate ester (0.25 g) at -78° C. was added MeMgC1 (0.4 mL, 3 M) in 50 THF, and the reaction mixture was warmed slowly to room temperature and stirred. The reaction was monitored by TLC. The reaction was quenched with Saturated aqueous NHCl (2 mL), diluted with EtOAc (5 mL) and the organic phase was gently evaporated. The residue was purified on 55 silica gel eluted with EtOAc/MeOH (9:2, V/v) to give 58 mg Preparation of (S)-t-butyl isobutyl sulfoxide: A THF (40 (79%) title product. mL) solution of (S)-tert-butyl (1R,2S)-aminoindanol mesi H NMR (CDC1): & 1.25 (s, 9H), 2.38 (s.3). 'C NMR tylene sulfonamide sulfinate (5.8 g) at -5°C. was slowly (CDC1): 8 22.52, 31.60, 52.62. added to iBuMgBr (10.5 mL, 2M) in ether. After addition, the reaction mixture was warmed to 10° C., stirred and the 60 reaction was monitored by TLC. The reaction was quenched 21 by aqueous NHCl, diluted with EtOAc (20 mL) and stirred. N The organic phased was washed with brine (20 mL). Evapo N ration of the solvent to dryness to afford the crude product 65 i that was purified on column eluted with EtOAc to give 1.9 g (88%) title product. US 7,256.297 B2 49 50 Preparation of (S)-picolinyl t-butylsulfoxide from (S)- independently substituted or unsubstituted alkyl, substituted tert-Butyl (1R, 2S)-aminoindanol 4-toluene sulfonamide or unsubstituted aralkyl, substituted or unsubstituted het sulfinate: To a picolinyl lithium solution (2 mL, 0.6 M) in eroalkyl, substituted or unsubstituted aryl, substituted or THF at -78° C. was added (S)-t-butyl-(1R,2S)-aminoin unsubstituted heterocycle; R and R together form a cyclic danol tosylate sulfinate (130 mg, 0.30 mmol). The mixture structure or each of R, and R is independently hydrogen, was warmed to room temperature and stirred until the substituted or unsubstituted alkyl, substituted or unsubsti starting material was consumed as monitored by TLC. The tuted aralkyl, substituted or unsubstituted heteroalkyl, sub reaction was quenched by aq. NaHCO, (20 mL) and diluted with ethyl acetate (20 mL), and the organic phase was stituted or unsubstituted aryl, or substituted or unsubstituted washed with water (20 mL) and brine (20 mL). The organic heterocycle; R and R, together form a cyclic structure or layer was concentrated in vacuo and the residue was purified 10 each of R and R, is independently hydrogen, Substituted or by chromatography eluted with ethyl acetate to yield 32 mg unsubstituted alkyl, substituted or unsubstituted aralkyl, of the desired product. substituted or unsubstituted heteroalkyl, substituted or "H NMR (300 MHz, CDC1): 8 1.19 (s.9H), 3.82 (d. 1H, unsubstituted aryl, or substituted or unsubstituted hetero J=12.3 Hz), 4.07 (d. 1H, J=12.3 Hz), 7.26 (m. 1H), 7.45 (d. cycle; and R is a polymer bound alkyl, aryl or heteroalkyl, 15 substituted or unsubstituted alkyl, substituted or unsubsti 1H, J=7.2 Hz), 7.72 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 8.63 (dd, tuted aralkyl, substituted or unsubstituted heteroalkyl, sub 1H, J=48, 0.9 Hz). 'C NMR (75 MHz, CDC1): 8 23.29, stituted or unsubstituted aryl, substituted or unsubstituted 54.19, 55.09, 123.19, 132.31, 137.19, 142.77, 150.12. ether, substituted or unsubstituted ester, substituted or unsubstituted ketone, substituted or unsubstituted phospho nate, Substituted or unsubstituted phosphonic acid ester, substituted or unsubstituted phosphinoyl, substituted or unsubstituted sulfide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfinyl imine, substituted or S -k unsubstituted heterocycle, or —NRRs, wherein Ra and Rs O together with the nitrogen atom to which they are attached 25 form a heterocycle or each of R and Rs is independently hydrogen, substituted or unsubstituted alkyl, substituted or Preparation of (R)-phenyl t-butylsulfoxide from (S)-tert unsubstituted heteroalkyl, substituted or unsubstituted Butyl (1R,2S)-aminoindanol mesitylene sulfonamide: A 50 aralkyl, substituted or unsubstituted aryl, substituted or mL flask was charged with (S)-tertbutyl-(1R,2S)-aminoin unsubstituted ether, substituted or unsubstituted sulfide, or danol mesitylene sulfonamide (1.12 g, 3.0 mmol) and THF 30 substituted or unsubstituted heterocycle. (3 mL) and the mixture was cooled to -20°C. To the mixture 2. The compound of claim 1, which has the following was added phenyl magnesium bromide (9 mL, 1.0 M in Structure: THF), the reaction mixture was stirred at 0° C. and the 3A reaction was monitored by THC. The reaction was quenched Ri' SORs by aqueous NaHCO (20 mL) and diluted with ethyl acetate 35 R M (70 mL), and the organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was concentrated Ra N in vacuo and the residue was purified by chromatography n -o eluted by 2:1 hexane:ethyl acetate to give 390 mg of R O (R)-phenyl t-butylsulfoxide. 40 R "H NMR (300 MHz, CDC1): 8 1.20 (s.9H), 7.53 (m,3H), R.' 7.63 (m, 3H). 'C NMR (75 MHz, CDC1): 8 23.04, 56.02, 126.57, 128.63, 131.40, 140.23. Anal. Calcd for CHOS: 3. The compound of claim 1, which has the structure: C, 65.89; H, 7.74; S, 17.59. Found: C, 65.91; H, 7.78; S, 17.65. Optical rotation: C=1.0, CHC1. C.’, +174.6 (lit. =+ 45 R , O.R. 175). N While the invention has been described with respect to + S-O. particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be R O R.' made without departing from the spirit and scope of the 50 invention as defined in the claims. Such modifications are 4. The compound of claim 3, which has one of the also intended to fall within the scope of the appended claims. following stereochemistries: The invention claimed is: 1. A compound of Formula 3: 55 R i SOR2TV-3 R i SOR2TV-3 R M R M N wN. (3) \, ... R" L + S-O + SI I IO R A R ? R ino? R 3. N R.' R.' n S-O 60 R i SOR2r.3 R i SOR2r.3 R c/ R M R M N N R \ N R" smo + SO Fif 65 R O R to wherein n is 0 to 3; L is SOR, wherein m is 0 to 3; R and R.' R.' R together form a cyclic structure or each of R and R is US 7,256.297 B2 51 52 11. The compound of claim 10, wherein R is halogenated -continued phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl, R SO2R3 R SO2R3 R 1 / R 1 / 4-(tert-butyl)phenyl, 2,4,6-triisopropylphenyl, phenyl or aN N 5 biphenyl. + S-O- + S-O- 12. The compound of claim 1, which is of the Formula 10: R c/ R "uno? R" R" R’ SOR3 R’ (10) R 1 / R 1 / 10 jok aN N O + S. O. + S. O. NN's 1 R c/ R "no? R" n-y- 5. The compound claim 1 wherein R is aryl or alkyl. 15 ex 6. The compound of claim 1 wherein R is aryl or alkyl. (R10)m 7. The compound of claim 1 wherein R is substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, or aryl. or a salt, Solvate, clathrate, or stereomerically pure form 8. The compound of claim 6, wherein R is halogenated 20 thereof, wherein each Ro is independently substituted or phenyl, 3-methylphenyl, 4-methylphenyl, 1,3,5-trimeth unsubstituted alkyl, substituted or unsubstituted aralkyl, ylphenyl, 4-(tert-butyl)phenyl, 2-mesityl, tolyl. 2,4,6-triso Substituted or unsubstituted aryl, a primary, secondary, or propylphenyl, phenyl or biphenyl. 9. The compound of claim 7 wherein R is 2-mesityl, tolyl tertiary amine, or a halogen atom; n is an integer of 1 to 4: or triisopropylphenyl. 25 and m is an integer of 0 to 4. 10. The compound of claim 1, which is of the Formula 9: 13. The compound of claim 12, wherein n is 1 and m is (9) 0, 1 or 2. SOR3 14. The compound of claim 13, wherein R is halogenated 30 phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl, 2,4,6-triisopropylphenyl, phenyl or biphenyl. 15. The compound of claim 10 or claim 12, wherein said 35 compound is stereomerically pure. or a salt, Solvate, clathrate, or stereomerically pure form thereof.